Keys to the switch of fat burning: stimuli that trigger the uncoupling protein 1 (UCP1) activation in adipose tissue

Gong, Dihong; Lei, Juanhong; He, Xudong; Hao, Junjie; Zhang, Fan; Huang, Xinya; Gu, Wen; Yang, Xinxin; Yu, Jie

doi:10.1186/s12944-024-02300-z

Review
Open access
Published: 28 September 2024

Keys to the switch of fat burning: stimuli that trigger the uncoupling protein 1 (UCP1) activation in adipose tissue

Dihong Gong¹^na1,
Juanhong Lei¹^na1,
Xudong He¹,
Junjie Hao¹,
Fan Zhang¹,
Xinya Huang¹,
Wen Gu¹,
Xinxin Yang¹ &
…
Jie Yu¹

Lipids in Health and Disease volume 23, Article number: 322 (2024) Cite this article

Metrics details

Abstract

As one of the main pathogenic factors of cardiovascular and cerebrovascular diseases, the incidence of metabolic diseases such as adiposity and metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing annually. It is urgent and crucial to find more therapeutic targets to treat these diseases. Mainly expressed in brown adipocytes, mitochondrial uncoupling protein 1 (UCP1) is key to the thermogenesis of classical brown adipose tissue (BAT). Furthermore, white adipose tissue (WAT) is likely to express more UCP1 and subsequently acquire the ability to undergo thermogenesis under certain stimuli. Therefore, targeting and activating UCP1 to promote increased BAT thermogenesis and browning of WAT are helpful in treating metabolic diseases, such as adiposity and MASLD. In this case, the stimuli that activate UCP1 are emerging. Therefore, we summarize the thermogenic stimuli that have activated UCP1 in recent decades, among which cold exposure is one of the stimuli first discovered to activate BAT thermogenesis. As a convenient and efficient therapy with few side effects and good metabolic benefits, physical exercise can also activate the expression of UCP1 in adipose tissue. Notably, for the first time, we have summarized and demonstrated the stimuli of traditional Chinese medicines that can activate UCP1, such as acupuncture, Chinese herbal formulas, and Chinese medicinal herbs. Moreover, pharmacological agents, functional foods, food ingredients, and the gut microbiota are also commonly associated with regulating and activating UCP1. The identification and analysis of UCP1 stimuli can greatly facilitate our understanding of adipose tissue thermogenesis, including the browning of WAT. Thus, it is more conducive to further research and therapy for glucose and lipid metabolism disorders.

Introduction

With the expansion of the economy and society, diseases related to glucose and lipid metabolism disorders, such as hyperlipidemia, adiposity, and MASLD, are increasing daily and have become vital factors that are hazardous to human health [1]. Adipose tissue plays a crucial role in the occurrence of metabolic diseases and has become a new direction in seeking treatments. There are two main types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). As a main source of thermogenesis in mammals, BAT can increase energy consumption through nonshivering thermogenesis promoted by UCP1. Therefore, BAT, especially UCP1, may become a potential therapeutic target for treating diseases such as obesity and other related metabolic diseases.

Moreover, studies have shown that brown-like adipocytes can also be found in WAT depots; these so-called “beige” or “brite” adipocytes can be observed only in the WAT of animals that have experienced cold or other stimuli [2]. Beige adipocytes have a morphology similar to that of brown adipocytes, such as multilocular lipid droplets, abundant mitochondria, and UCP1 expression; these properties endow beige adipocytes with the same functions as brown adipocytes. Brown adipocytes express a relatively large quantity of UCP1 even with no stimulation, but beige adipocytes can only produce UCP1 under stimulated conditions. Brown and beige adipocytes both possess the ability to metabolize glucose and fats to generate heat. In particular, brite adipocytes can exhibit equivalent levels of UCP1 expression to brown adipocytes and engage in UCP1-dependent uncoupled respiration under full activation [3].

Essentially, stimuli such as cold, exercise, and pharmaceutical agents have the potential to trigger the activation of UCP1 within brown and white fat cells. This activation can subsequently increase heat production, improving conditions such as adiposity. The distribution and fat mass of WAT and BAT in obese and healthy individuals, the stimuli that influence the expression level of UCP1, and the structure of all adipocytes are shown in Fig. 1.

The thermogenic role of brown or brite adipocytes relies significantly on the stimulation of UCP1 [6]. When activated, UCP1 dissipates the proton gradient created by the electron transport chain [7]. UCP1 is the pivotal factor for the heat production of classical BAT and beige adipocytes. Nevertheless, owing to intrinsic inhibitory mechanisms, UCP1 remains quiescent and fails to generate heat under nonactivated situations [8]. Activating UCP1 is one of the methods used to increase the heat consumption of BAT. Moreover, inducing the production of brite adipocytes, namely, promoting the generation of UCP1 in WAT, is another way to promote thermogenesis. Researchers previously reported that there is more BAT in newborns than in adults, so BAT is critical for maintaining body temperature in infants. However, it cannot increase the heat production of adults. Owing to the development of 18 F-FDG-PET technology and other measurement techniques, emerging studies have shown that adults also have substantial depots of 18 F-FDG PET-positive adipocytes and UCP1 + adipose cells, i.e., BAT [9], and when exposed to stimulus situations, these tissues can absorb glucose [10,11,12,13,14].

According to these studies, activating UCP1 in BAT and inducing UCP1 expression in WAT to stimulate the browning of WAT are key methods for increasing heat production. Furthermore, targeting UCP1 could offer a strategy for treating metabolic diseases. Researchers may be interested in the stimuli that activate UCP1 [15]. Therefore, this paper aims to update and summarize the experimental and clinical evidence of stimuli that can activate UCP1. Moreover, for the first time, we have summarized the stimuli of traditional Chinese medicine that can activate UCP1, such as acupuncture, Chinese herbal formulas, and Chinese medicinal herbs. We hope that this perspective can provide ideas and prospects for targeting UCP1 to treat metabolic diseases.

Characterization of UCP1

The mitochondrial inner membrane contains uncoupling proteins (UCPs), which act as metabolite transporters, facilitating controlled dissipation of the proton gradient produced by the respiratory chain [16]. These proteins typically have molecular masses ranging from 31 to 34 kDa. Additionally, five isoforms of UCPs exist, spanning from UCP1 to UCP5, which are distributed across various species and tissues, including animals, plants, fungi, and protozoa [17, 18]. For example, UCP1 is expressed mainly in brown adipocytes of mammals. UCP2 is widely distributed among most cell types. UCP3, on the other hand, is expressed only in skeletal muscle and BAT, whereas UCP4 and UCP5 are exclusively expressed in the brain [16]. Although UCP1 is pivotal for no-shivering thermogenesis and has been extensively explored by numerous researchers, UCP2 is postulated to be involved in lipid metabolism, and UCP3 could afford protection against lipid-induced oxidative damage [19]; however, the characterization and function or transport properties of UCPs, particularly UCP1, still require further examination.

The structure of UCP1

The structure of a protein determines its function. Like other UCPs, UCP1 features a structural pattern consisting of three reiterated components. Within each module, a sequence of amino acids elegantly forms a loop that traverses the membrane twice, thereby creating six transmembrane helices, labeled TM1 to TM6 [20]. Conserved proline residues create bends in odd-numbered helices, whereas conserved glycines facilitate polypeptide chain mobility. Helices 4 and 6 also contain conserved prolines, contributing to structural variations [21]. Many articles have exhaustively examined and elucidated the structural characteristics of UCP1, providing a comprehensive understanding of its unique features [16, 20,21,22].

As a metabolite carrier and thermogenin, UCP1 can transport fatty acids and nucleotides across the inner membrane of the mitochondrion through the coordinated movements of its helices, which control the proton-conducting activity of UCP1 [22]. Usually, the proton-conducting ability of UCP1 is inhibited by purine nucleotides, and when the concentration of free fatty acids is elevated in BAT, the inhibitory effect of purine nucleotides on UCP1 is controlled, and UCP1 can be activated for heat production [22].

The function of UCP1

UCP1, the most extensively studied isoform of UCP, is expressed predominantly in brown adipocytes and beige adipocytes of various mammalian species, including mice, rats, and humans. In addition, it has been found in the liver, kidney, and brain of certain fish species, indicating its widespread distribution and diverse physiological roles [23]. Numerous studies suggest that the core of BAT thermogenesis and overall energy balance lies in the direct control of UCP1 protein function. Upon activation, UCP1 catalyzes heat production through the dispersion of the proton gradient energy; i.e., after UCP1 facilitates proton escape, the acquired energy cannot be stored as ATP but is instead released as heat [24, 25]. Free fatty acids function as substrates that trigger the activation of UCP1 [26]. Upon activation through the binding of a fatty acid, UCP1 facilitates the transfer of protons from the membrane space into the mitochondrial matrix [27]. Furthermore, concurrent with the activation of UCP1, there is an increased utilization of glucose [26, 28]. Hence, during UCP1-mediated thermogenesis, the consumption of fatty acids and glucose also increases, contributing significantly to the improvement of adiposity and associated metabolic diseases.

In addition, to detect brite adipocytes among white adipocytes, we must identify the ectopic expression of UCP1. In other words, UCP1 is a key transcription factor that promotes WAT browning. Therefore, facilitating the elevation of UCP1 in adipose tissue is conducive to augmenting thermogenesis, thereby improving obesity or related metabolic diseases [29]. Conversely, the absence of UCP1 leads to a notable decrease in BAT heat production [30]. As an illustrative example, UCP1 knockout neonatal mice presented lower skin temperatures surrounding the interscapular region and exhibited weight loss upon weaning. This observation underscores the crucial role of UCP1 as a bright regulatory target for maintaining body temperature during the early stages of life [31]. Moreover, the absence of UCP1 hinders BAT thermogenesis in both neonatal and mature mice, as determined through infrared imaging and indirect calorimetry, respectively [32].

In conclusion, enhancing thermogenic UCP1 and BAT activity in humans to increase energy expenditure could be highly beneficial in addressing metabolic diseases, such as adiposity and MASLD. The search for UCP1 stimuli is necessary and urgent.

Physical and environmental factors–cold stimulation

Under conditions of thermoneutrality, WAT depots primarily lack UCP1, resulting in a significant deficiency. However, when animals are chronically exposed to cold conditions, they undergo acclimation processes that involve the expansion of brown adipocytes and the upregulation of UCP1, enabling them to generate heat effectively [9]. In other words, exposure to cold conditions can stimulate the production of new thermogenic adipocytes in adipose tissues [33]. Consistent with these findings, numerous subsequent studies have corroborated these results [34]. Aleksandra et al. [35] reported an increase in UCP1 mRNA in rpWAT after exposure to cold. Walden et al. [36, 37] further demonstrated that when animals are maintained at room temperature (20℃), UCP1 levels in adipose tissue are minimal. However, when animals are placed in cold conditions (4℃), a remarkable increase in UCP1 is observed in fat tissue.

Cold exposure initiates the heat production of BAT via UCP1 activation, which in turn triggers significant modifications in the metabolism of glucose, lipids, and amino acids. Okamatsu-Ogura Y et al. [38] demonstrated that in wild-type mice, the levels of glycolytic metabolites increase significantly after exposure to cold temperatures. However, in UCP1-KO mice, the levels of these metabolites are notably decreased. These findings suggest that cold conditions trigger UCP1-stimulated thermogenesis in adipose tissue, which in turn has a profound effect on glucose utilization. Furthermore, exposure to cold primarily stimulates the metabolism of amino acids in adipose tissue, specifically enhancing glutamine utilization in a UCP1-dependent manner. This may be one of the mechanisms mediating the improvement in adiposity. However, Sepa-Kishi DM et al. [39] recently presented groundbreaking findings that, despite the marked elevation of UCP1 levels in inguinal WAT and the induction of browning in this adipose depot upon exposure to cold, adipocytes from this depot fail to exhibit an increase in glucose and lipid oxidation through UCP1-mediated mitochondrial uncoupling. These results clearly emphasize the imperative need for further investigation into the intricate mechanism by which UCP1 influences the regulation of glycolipid metabolism.

Regarding the mechanism underlying the elevation of UCP1 through cold exposure, the sympathetic nervous system (SNS)-catecholamine (CA)-UCP1 pathway plays a pivotal role [40]. When sympathetic nerves are stimulated by cold exposure, the SNS releases the CA (epinephrine and norepinephrine). Furthermore, CA activates protein kinase A (PKA) via adrenoreceptors (ARs), such as β3-AR. Subsequently, PKA significantly impacts UCP1 activity by orchestrating various cellular processes. These include AIDA, a protein containing a C2 domain known for its ability to counter obesity induced by diet, as well as the fatty acids generated through the breakdown of lipid droplets inside adipocytes [27, 41] (fatty acids, as the substrate of UCP1, can activate UCP1 directly and overcome the inhibition of purine nucleotides on UCP1 [27]). This cascade of events initiates a diverse array of alterations in adipose tissue, ultimately resulting in increased heat production. Moreover, the PGC-1α–PPARγ signaling cascade plays a pivotal role in inducing and activating UCP1 expression in WAT during cold exposure [35] (Fig. 2).

Importantly, maintaining a sustained thermogenic response and ensuring a sufficient population of brown-like adipocytes possessing thermogenic functions are crucial for the browning process of WAT. Both aspects above that induce browning are equally important and could exert a significant impact on maintaining overall energy balance and regulating body mass in the long run [35]. However, cold exposure can cause initial, dramatic, but transitory nonselective browning of most adipocytes in retroperitoneal WAT (rWAT), but few adipocytes maintain brown-like characteristics in the long term [35]. Therefore, cold stimulation may have limited significance in stimulating WAT browning and increasing heat production capacity.

In addition, its underlying mechanism for enhancing heat production remains worthy of further exploration. For example, the combination of cold exposure with other browning agents, such as pioglitazone, can significantly increase the heat production capacity of adipose tissue [42]. Alternatively, the topical use of a pharmacological cold mimic such as L-menthol, a transient receptor potential (TRPM8) cation channel subfamily M member 8 (TRPM8)) agonist, can facilitate the thermogenesis of brown fat via the activation of TRPM8 and UCP1 and the release of norepinephrine. These findings indicate that pharmacological cold mimetics, which are capable of simulating cold conditions, can achieve effects similar to those induced by actual cold exposure. The utilization of agents that mimic the natural activation of BAT presents promising avenues for addressing obesity while minimizing the overall impact on the body. Furthermore, it may circumvent some of the limitations associated with traditional cold induction methods [43].

Furthermore, it is crucial to recognize that exposure to cold temperatures poses a potential risk of promoting the growth and instability of atherosclerotic plaques, a process that is facilitated by UCP1-mediated lipolysis [44]. Therefore, for individuals who already have preatherosclerotic lesions, the thermogenesis of BAT induced by cold exposure might not necessarily be beneficial for improving certain diseases. Moreover, some scholars have proposed that increasing global temperatures could diminish BAT activity [45]. At thermoneutrality, UCP1 also fails to provide protection against obesity or other metabolic diseases induced by dietary factors [32]. Therefore, establishing reliable animal models under thermoneutral conditions, which can help researchers assess diet and agent capacity for thermogenesis precisely, is urgently needed [46].

Physical and environmental factors–exercises

Engaging in physical exercise can enhance cardiometabolic health, improve pregnancy complications [47], and promote weight loss by establishing a caloric deficit [48]. Even if weight and body composition remain unchanged, engaging in physical exercise still provides beneficial metabolic effects. They are often used as a practical way to manage adiposity and other metabolic diseases. In addition, exercise can decrease BAT whitening in obese individuals [49] and is also a well-known trigger for WAT browning.

Exercise can be broadly categorized into two types: aerobic exercise training (AET) and resistance exercise training (RET). AET encompasses both constant-moderate endurance training (END) and high-intensity interval training (HIIT). Both END and HIIT are renowned for their capacity to improve overall physical fitness, including enhancing body composition, vascular function, and glucose regulation [50,51,52]. Although both exercise programs can confer metabolic benefits, only HIIT can increase UCP1 in adipose tissue [53, 54]. Moreover, high-intensity exercise is more likely to promote systemic adrenergic activity in the body [55] and might preferentially induce browning of WAT after HIIT over END. HIIT also increases lactate and β-hydroxybutyrate; this may be the reason for the increase in heat production (the upregulation of thermogenic factor (UCP1) in WAT) [54]. Acute swimming also has the same effect. As in Cho’s study, following a session of acute swimming exercise, the UCP1 expression level in sWAT was increased [56].

Compared with AET, RET presented a lower body weight. Moreover, RET showed beneficial effects similar to those of AET, including a reduction in iWAT and rpWAT sizes, activation of UCP1, and upregulation of specific brown adipocyte phenotype genes. These interventions can effectively stimulate the browning process in WAT [57]. Researchers further revealed that HIIT can attenuate skeletal muscle loss and enhance locomotor abilities through the PGC-1α‒FNDC5‒UCP1 signal transduction pathways [58].

Moreover, iWAT is more sensitive to the regulatory impacts of physical exercise on UCP1 than is epididymal WAT (eWAT) [59,60,61]. The intensity of exercise can also influence the browning process of WAT. According to Tanimura R [62], there was a notable elevation in the protein expression levels of UCP1 in iWAT and FGF21 in skeletal muscle compared with low-intensity running.

Exercise likely triggers multiple mechanisms to facilitate the browning of WAT. First, engaging in physical exercise as a primary measure can potentially initiate the browning process by diminishing hypothalamic inflammation and enhancing gene expression in POMC neurons [63]. Furthermore, physical activity activates the SNS, resulting in the release of norepinephrine from the SNS that binds to β-AR receptors, thereby inducing adipose tissue browning and facilitating increased heat production [64]. Moreover, irisin, a myokine secreted from skeletal muscle, can also regulate the browning of WAT [65,66,67]. Physical exercise stimulates irisin secretion [68, 69], which affects thermogenesis, including the PPAR-α/UCP1 pathway. Moreover, PGC-1α also plays a crucial role in the stimulation of irisin secretion in skeletal muscle induced by exercise and exercise training, as does the upregulation of UCP1 in WAT [59, 70]. (The partial mechanisms by which physical exercise activates UCP1 are shown in Fig. 3.)

Interestingly, in studies of humans, researchers have reported some differences [71, 72]. After an eight-week program combining physical training, consisting of alternating 30 s strength and aerobic exercises conducted three times weekly for 60 min each session, notable improvements were observed in the resting metabolic rate, lipid oxidation, and overall physical performance. However, there was a lower expression of UCP1 mRNA in the WAT of obese women, which means that physical training cannot promote thermogenesis and WAT browning in the human body. This may be ascribed to a number of factors, which include the length of the training period, the differences between animal and human “house” conditions, the inherent differences between species, or perhaps the browning occurring in different WAT depots [73]. In addition, detection methods have many limitations [74]. Obtaining multiple biopsies from the same location, particularly from human BAT, presents challenges. Moreover, scholars have demonstrated that the enhanced thermogenic response triggered by physical activity could be a transient occurrence [64]. Consequently, the unaltered or decreased heat generation in BAT might represent a “forced choice” during exercise [75] because the thermogenesis of adipose tissue leads to an elevated core body temperature, which is detrimental to exercise. Furthermore, the process of thermogenesis is fuelled by glucose and the oxidation of fatty acids, leading to competition for energy resources with skeletal muscles during physical activity. Therefore, it is plausible that UCP1 is expressed at low levels after exercise/exercise interventions [64].

To summarize, findings from rodent studies demonstrate that engaging in physical activity can upregulate the expression level of UCP1. This, in turn, induces WAT browning, enhances the heat production of BAT, and elevates metabolic rates within the adipose tissue [76]. Physical exercise is an effective means to control metabolic diseases, such as adiposity and MASLD, even without significant weight loss.

However, the effects of improvements in physical activity on thermogenesis in the human body are controversial and need to be further studied. This may require more sophisticated clinical trials for confirmation (strictly controlled experimental conditions and perfect experimental design).

Factors related to traditional Chinese medicine

Acupuncture

Acupuncture is a traditional Chinese medicine. Under the guidance of traditional Chinese medicine theories, the doctor pricks the needle into the patient’s body (the piercing point is called the human acupoint, referred to as the acupoint) through twisting, lifting, and other acupuncture techniques to stimulate the human acupoint to treat the disease. As a traditional Chinese medicine therapy, acupuncture has a history of thousands of years in China. It boasts numerous advantages, including straightforward operation, minimal adverse reactions, and the ability to regulate multiple targets. It is widely employed to alleviate various metabolic disorders, particularly adiposity, and has demonstrated exceptional therapeutic efficacy [77, 78].

The regulation of UCP1 serves as one of the underlying mechanisms of acupuncture treatment for numerous diseases, including adiposity and MASLD. Acupuncture effectively upregulates UCP1, thereby facilitating the browning of WAT, enhancing energy metabolism, and mitigating fat accumulation. A study on the treatment of obesity by electroacupuncture revealed that stimulation of acupuncture points (“Guan Yuan,” bilateral “Shenshu,” “Tianshu,” and “Fenglong”) in obese rats could increase the mitochondrial UCP1 expression level in fat tissue and facilitate the improvement of lipid metabolism [79]. Other studies have consistently corroborated this finding [80,81,82,83,84].

Furthermore, auricular acupuncture (AA) and acupoint catgut embedding (ACE), as extensions of acupuncture, can also treat obesity by regulating UCP1 [85, 86]. The stimulation of auricular points triggers a response in the corresponding ear acupoints associated with the viscera, thereby achieving the desired therapeutic effect. ACE involves the embedding of disposable, sterile, and absorbable acupoint threads into acupoints, resulting in a comprehensive and lasting effect on the acupoint and the body. ACE, with the long-acting needle feeling of a “thread instead of a needle,” can improve the excitability and conductivity of acupoints. Therefore, ACE represents a significant extension and advancement of traditional acupuncture techniques. It has gained widespread application in China to manage many conditions, such as adiposity and polycystic ovary syndrome. For example, researchers treated perimenopausal obesity in female rats with acupoint embedding and discovered that acupoint embedding at the Shenshu, Pishu, and Ganshu points could increase UCP1 expression levels and promote heat production, thus strengthening energy metabolism and playing an essential role in preventing and treating perimenopausal obesity [86].

In short, acupuncture and catgut embedding can dredge meridians, regulate qi and blood, remove dampness and eliminate turbidity, which plays an overall regulatory role in the human body. The activation of UCP1 may be only part of the mechanism by which it exerts its therapeutic effect. (The effects of acupuncture on UCP1 are shown in Table 1; acupoints are shown in Fig. 4.)

Table 1 Acupuncture

Full size table

Chinese herbal formulas

Traditional Chinese medicine is a profound and extensive historical heritage of China. For thousands of years, Chinese medicine has eliminated disease and brought health to Chinese people, which has occupied a significant position in China’s medical system. The Chinese herbal formula refers to a group of drugs that are meticulously mixed according to the principle of composition after the treatment method is determined on the basis of syndrome differentiation. Chinese herbal formulas, with their multicomponent and multitarget advantages, can effectively regulate numerous targets through diverse pathways. One fascinating mechanism underlying its antiobesity effects lies in the activation of UCP1 in BAT and the induction of UCP1 expression in WAT, thereby promoting WAT browning and enhancing adipose tissue thermogenesis.

Bofutsushosan, also known as Fangfengtongshengsan, was first documented in XuanMingLunFang by Liu WanSu in the Jin dynasty. Studies have shown that bactutosan can improve obesity [87] and MASLD [74]. Chen and colleagues demonstrated that bofutsushosan can facilitate the upregulation of UCP1 genes in BAT and primary brown adipocytes via the β3-adrenergic signaling pathway, which is associated with thermogenesis and energy consumption in BAT. As a result, bactutosan effectively improves serum biochemical indices and significantly reduces body weight in obese mice [88]. Furthermore, Akagiri’s study provides further evidence supporting this mechanism of Bofutsushosan [89].

Gui Zhi Tang, a famous formula documented in the famous Treatise on Cold Damage and Miscellaneous Diseases, is usually used to remove exterior cold. Jiang Gui Fang, derived from Gui Zhi Tang, is also widely used to relieve cold because of its effects on heat production and the protection of vital organs in cold environments. ZU et al. [90] reported that Jiang Gui Fang can induce eWAT browning and facilitate interscapular BAT (iBAT) heat production by increasing UCP1 and PGC-1α expression. This ultimately results in an elevation of the core temperature in mice, irrespective of whether they are exposed to short-term or long-term cold conditions, thereby facilitating improved lipid and glucose metabolism. Moreover, Chinese medicinal herbs such as Ephedrae Herba, Schizonepetae Herba, Zingiberis Rhizoma, and Cinnamomi Cortex possess the properties of xin and wen and can disperse cold and warm meridians and collaterals. Moreover, the components of those prescriptions, namely, Zingiberis Rhizoma, Cinnamomi Cortex, and Cinnamomi Ramulus, also exhibit promising potential to activate thermogenesis in adipose tissue. This could explain the mechanisms underlying how these formulas enhance heat production and contribute to lipid-lowering effects. Liu’s [91] study confirms this hypothesis. Treating cold-exposed mice with the Rougui-Ganjiang herb pair can increase metabolism and increase heat production in BAT, maintaining body temperature by activating the cAMP-PPARα/γ-PGC-1α-UCP1 signaling pathway.

Moreover, many other formulas also activate UCP1 and thermogenesis in adipose tissue [91,92,93,94,95,96] (Fig. 5).

As stated in Huangdi’s canon of medicine: “Only when yin is at peace and yang is compact can essence spirit be normal.” Prescriptions are composed under the guidance of specific theories and principles of traditional Chinese medicine, such as the theory of Yin and Yang, and the herbs in prescriptions can interact with each other to regulate the thermogenesis gene UCP1, which exerts a balance between BAT and WAT. In other words, the formula regulates the balance of Yin and Yang in the human body through the regulation of UCP1, which achieves an overall regulatory effect on the human body.

Chinese medicinal herbs and their bioactive compounds

The effectiveness of Chinese medicinal herbs has been confirmed continuously in history, and modern research has revealed that the efficacy of Chinese medicinal herbs is based mainly on bioactive compounds of Chinese medicinal herbs—monomers of Chinese medicinal herbs. Monomers have the advantages of clear chemical structures, abundant pharmacological activities, and few side effects. Moreover, compared with synthetic compounds, monomers exhibit superior structural diversity and biological activities, which allows them to target specific biological processes with greater precision and demonstrate enhanced therapeutic efficacy. For example, artemisinin is used in Artemisia apiacea, ginsenosides are used in Ginseng Radix et Rhizoma, and so on.

Chinese medicinal herbs are often used to regulate glucose and lipid metabolism disorders; treat hyperlipidemia, obesity, and diabetes; and improve cardiovascular and cerebrovascular diseases. Among these, Cinnamomi Cortex, Ginseng Radix et Rhizoma, and Coptidis Rhizoma are commonly used in clinical practice. Moreover, studies have revealed that monomers extracted from these Chinese medicinal herbs, including berberine, not only decrease blood lipids and mitigate atherosclerosis but also exert protective effects on the cardiovascular and cerebrovascular systems. Therefore, harnessing the bioactive compounds of Chinese medicinal herbs to facilitate the upregulation of UCP1 and thermogenesis of fat tissue represents a safe and innovative approach in the fight against metabolic diseases (Fig. 6).

Ginseng radix et rhizoma

Ginseng Radix et Rhizoma, a Chinese medicinal herb in China, is highly valued for its remarkable ability to replenish Qi, promote fluid, and soothe nerves. Moreover, black ginseng (BG) exhibits numerous substantial biological activities, among which are its antiobesity and antidiabetes properties [97]; BG enhances the expression level of the critical thermogenesis protein UCP1, which may represent one of the underlying mechanisms responsible for its beneficial effects [98]. In addition, the procedure for producing BG involves drying and steaming Ginseng Radix et Rhizoma. Interestingly, the steaming process can promote the generation of different ginsenosides, including Rb1 and Rg1 [99]. Moreover, ginsenosides Rb1 and Rg1 [100] can increase the UCP1 expression level in subcutaneous white adipocytes from C57BL/6 mice as well as 3T3-L1 cells. Consequently, they play a pivotal role in combating obesity by facilitating adipocyte browning. More importantly, the saponins found in the stems and leaves of ginseng can also facilitate the upregulation and activation of UCP1 and UCP3 within adipose tissues. This phenomenon has demonstrated remarkable efficacy in combating obesity in diet-induced obese mice [101].

Coptidis Rhizoma

Coptidis Rhizoma, renowned for its ability to clear heat, dry dampness, purge fire, and detoxify, is commonly utilized in the treatment of diarrhea, icterus, and adiposity. Berberine (BBR) is the active compound isolated from Coptidis Rhizoma. As early as two decades ago, researchers amply demonstrated that BBR is a novel antihyperlipidemic medication through animal experiments and clinical trials [102]. Numerous studies have revealed the pivotal role of BBR in enhancing glucolipid metabolism through its ability to modulate adipose tissue. Zhang et al. [103] reported that BBR can inhibit WAT accumulation and facilitate heat generation in fat tissue by increasing thermogenic gene expression. In addition, BBR can affect UCP1 promoter activity and regulate UCP1 expression levels by changing the configuration of the G-quadruplex formed by the UCP1 gene oligo fragment [104]. Wang et al. [105] have additionally shown that berberine has the ability to trigger the AMPK/SIRT1 pathway, which is responsible for energy metabolism, thereby increasing the deacetylation level of PPARγ. This process not only facilitates the restructuring of adipose tissue but also significantly enhances the expression of the thermogenic protein UCP1. The experimental findings above suggest that BBR potentially possesses therapeutic benefits and pharmacological properties in combating obesity [106] and that UCP1 is the main target of berberine in regulating the thermogenesis of adipose tissue.

Zingberis rhizoma recens

Zingiberis Rhizoma Recens is a widely utilized herb across numerous countries, including China, India, Nigeria, Australia, and Jamaica [107]. As a traditional Chinese herb, Zingberis Rhizoma Recens can promote sweating, improve exterior cold and warm stomachs, stop vomiting, warm the lungs, and stop coughing. Zingiberis Rhizoma Recens is extensively utilized to treat various ailments, including the common cold and rheumatism. Furthermore, much evidence has shown that Zingberis Rhizoma Recens possesses multiple bioactive compounds, such as zingerone and 6-gingerol [108]. These bioactive compounds all possess the potential to activate UCP1.

Derived from Zingberis Rhizoma Recens, zingerone is a bioactive ketone with various pharmacological properties. These include antioxidative, antimicrobial [108], and antiobesity effects [109, 110]. In addition, many scholars have demonstrated that zingerone can also upregulate UCP1 expression and subsequently activate thermogenesis in adipose tissue. Li et al. demonstrated that zingerone treatment could bind with PPARα. This interaction subsequently resulted in elevated levels of brown adipocyte-specific markers, including UCP1 and PGC-1α, in iWAT [111]. In addition, as a functional polyphenol of ginger, 6-gingerol can also increase the expression of the critical browning-specific marker (UCP1) through an AMPK-dependent pathway, thereby promoting mitochondrial biogenesis in 3T3-L1 adipocytes and browning [112].

Glycyrrhizae radix et rhizoma

Glycyrrhizae Radix et Rhizoma, a traditional Chinese herb, is widely used in most formulas in China. Glycyrrhizae Radix et Rhizoma possesses a range of beneficial properties, including replenishing the spleen Qi, clearing heat, relieving toxicity, expelling phlegm, and suppressing coughing. Modern experimental studies have also shown that Glycyrrhizae Radix et Rhizoma has anti-inflammatory, antioxidant, and anticancer effects. Moreover, scholars have demonstrated that extracts of Glycyrrhizae Radix et Rhizoma have the potential to significantly facilitate the upregulation of UCP1 in the BAT of obese mice [113]. In addition, licochalcone A, a unique chalcone compound extracted from Glycyrrhizae radix et rhizoma, can increase the levels of BAT indicators such as UCP1, PRDM16, and PGC-1α in inguinal WAT [114]. This discovery may provide insight into the mechanisms underlying how Glycyrrhizae Radix et Rhizoma facilitates the browning of WAT and contributes to its fundamental antiobesity effect.

Cinnamomi cortex

The Cinnamomi cortex tonifies yang, warms the meridian, dissipates cold, and relieves pain. Numerous ancient formulas in China contain this Cinnamomi Cortex, including the renowned YouGuiyin and ShenQiWan. The Cinnamomi cortex can benefit and tonify Yang, which allows it to activate thermogenesis. Li et al. reported that the extract of Cinnamomi cortex is capable of increasing the expression of thermogenic proteins, including UCP1, PGC1-α, and PRDM16, in both iBAT and iWAT through the activation of the AMPK/SIRT1 signaling pathway [115], thereby promoting the browning of iWAT and increasing nonshivering thermogenesis.

Moreover, cinnamaldehyde, a bioactive constituent of the Cinnamomi cortex, has been shown to increase UCP1 in white adipose water (WAT) and facilitate heat production [116, 117]. Neto et al. demonstrated that cinnamaldehyde can reduce BAT whitening and trigger the expression of thermogenesis markers (PPARγ, PGC1-α, and UCP1) by stimulating FGF21 expression in BAT [117]. Furthermore, trans-cinnamic acid, another bioactive constituent of the Cinnamomi cortex, can facilitate the browning of white adipocytes by stimulating the β3-AR and AMPK signaling pathways and increasing the UCP1 expression level [118].

Menthae Haplocalycis Herba

Menthae Haplocalycis Herba effectively evacuates wind heat and alleviates liver qi stagnation, providing relief for throat discomfort. Therefore, Menthae Haplocalycis Herba is extensively utilized to treat various ailments, such as rubella, headache, and the wind-heat type common cold.

Menthol, derived from the Menthae Haplocalycis Herba, acts as a cooling agent and induces a refreshing sensation upon application. Adipose tissues can absorb it through oral and topical routes, specifically via serum absorption and direct application. Studies have demonstrated that menthol can combat obesity via a glucagon-dependent mechanism controlled and mediated by TRPM8 [119], along with elevated heat production in adipose tissue [120]. Furthermore, the administration of bioavailable doses of menthol can promote the upregulation of UCP1 and other browning markers, which promote increases in energy expenditure [121]. This function of menthol is facilitated by TRPM8 in adipocytes.

Notably, however, oral menthol has little effect on humans [120]. Fortunately, topical menthol application has unexpected effects, including elevated core body temperature and improved metabolic rates [120]. This may be the direction of further research and clinical application. Mckie et al. confirmed that applying menthol to the skin could facilitate the release of norepinephrine from the SNS, which innervates BAT by activating TRPM8, ultimately enhancing UCP1-dependent thermogenesis [43].

Others

Numerous other bioactive compounds derived from Chinese medicinal herbs can induce thermogenesis by regulating the thermogenic protein UCP1. For example, Loureirin B (LB), a prominent flavonoid compound derived from Sanguis Draxonis, can increase the ratio of U3 polyunsaturated fatty acids (PUFAs) in adipose tissue. Consequently, this results in the activation of the pivotal lipid receptor GPR120, thereby triggering the browning process in WAT and stimulating BAT thermogenesis by increasing UCP1 expression [122]. Trans-anethole, a compound known for its flavor-enhancing properties, can be extracted from the essential oils of more than 20 different plant species. These include fennel, anise, and star anise [123, 124]. Kang et al. reported that trans-anethole can combat obesity induced by a HFD in a mouse model because trans-anethole can increase the brown fat-specific genes Prdm16 and Ucp1 [124]. Curcumin, which is extracted from the tropical plant Curcuma longa, can increase UCP1 in fat tissue and induce WAT browning [125, 126]. Baicalein, a primary bioactive flavonoid in the root of Scutellaria baicalens, has been demonstrated to promote WAT browning and activate BAT through the upregulation of UCP1 expression [127].

In conclusion, Chinese medicinal herbs and their bioactive compounds increase UCP1 expression and energy consumption, thereby serving as potential measures against metabolic diseases, such as obesity. Moreover, although the involvement of Chinese medicinal herbs in heat production has been demonstrated in small rodents, only limited information is currently available in humans, and the animal experimental design needs to be further perfected. For example, the control should be added to confirm that the perceived benefits to health conditions treated with TCM remedies are not subject to placebo effects.

Functional food and food ingredients

Functional food

Tea

Tea is classified into three primary types on the basis of its processing technique and degree of fermentation: nonfermented tea, partially fermented tea, and fully fermented tea. Tea is universally acknowledged for its diverse positive impacts on human health, including reducing fat mass and body weight and regulating glycolipid metabolism [128]. Moreover, numerous studies [129,130,131] have shown that tea can promote thermogenesis and suppress adiposity by increasing the UCP1 expression level in adipose tissue.

Green tea (GT), a nonfermented tea, is widely used worldwide. Considerable research has shown that green tea promotes a thermogenic phenotype by stimulating WAT browning and reducing BAT whitening [130,131,132,133]. For example, Neyrinck AM et al. reported that GT supplementation significantly elevates the expression of PGC-α, PRDM16, and UCP1, triggers WAT browning, and reduces fat storage, which improves adiposity [131]. Some researchers subsequently carried out further studies and confirmed the same results.

Various partially and fully fermented teas, including oolong tea, yellow tea, and black tea, can attenuate adiposity through mechanisms linked to the UCP1 pathway. For example, oolong tea, pu-erh tea, and black tea can promote the phosphorylation of the critical metabolic regulator AMPK and upregulate UCP1, which results in WAT browning and improved adiposity [129]. Another study has shown that oolong tea can also decrease adipocyte size, reduce fatty acid synthase protein expression, and increase thermogenesis-related protein (PGC-1α and UCP1) expression in eWAT, which can regulate lipid metabolism and reduce weight [134]. In addition, yellow tea (fermented tea) supplementation strongly facilitates the thermogenic program in BAT and sWAT, accompanied by increased body temperature. The underlying molecular mechanism involves the enhancement of mitochondrial biogenesis and the upregulation of the thermogenic gene Ucp1 by yellow tea [135].

Interestingly, there is a unique type of fermented dark tea, namely, Fu brick tea (FBT). Throughout the fermentation process of FBT, the predominant fungus, E. cristatum, generates the “golden flower,” which blossoms atop the surface of the tea. As a probiotic, E. cristatum confers FBT with the ability to increase glucolipid metabolism, thereby serving as a crucial criterion for assessing the quality of tea. Studies have indicated that continuous consumption of E. cristatum can effectively increase heat production by increasing UCP1 expression levels in both BAT and inguinal WAT [136]. Theabrownin (TB) derived from FBT also has notable efficacy in enhancing thermogenesis through activating the AMPK-PGC-1α signaling pathway and increasing the levels of UCP1 [137]. These studies suggest that FBT has significant potential in regulating thermogenesis, enhancing glycolipid metabolism, and combating obesity.

Seeds

Seaweeds, which are widely utilized as traditional foods, are rich in numerous nutritional components, including polyphenols, fibers, and various minerals. The antiobesity effects of the abundant ingredients present in seaweed have been extensively researched. Many seaweeds, including S. lomentaria (SL) and P. telfairiae (PT), can improve adiposity by activating the thermogenesis gene UCP1. For example, Yan et al. demonstrated that SL extract can increase the expression of UCP1 in vivo and p-AMPK/AMPK and UCP1 expression in vitro, which promotes thermogenesis in adipose tissue and ameliorates obesity in mice [138]. Sargassum thunbergii (ST), a type of edible brown algae, has been found to possess the ability to enhance critical protein (UCP1) expression, as demonstrated by Kim [139]. Moreover, ST can effectively decrease the expression level of PPARγ in WAT and increase the expression level of critical genes (Ucp1 and Ucp3) in BAT [140], indicating its antiobesity effects. Plocamium telfairiae (PT), another common seaweed, has been shown to effectively lower WAT weight while increasing the UCP1 expression level in BAT [141].

In summary, the activating effects of seaweed on UCP1 have been validated through rigorous experiments. There is also a need for further study to elucidate the underlying mechanisms of seaweed in humans.

Food ingredients

A diverse array of food ingredients, particularly those found in tea, fruits, vegetables, and condiments, have been shown to have the potential to increase energy expenditure, decrease fat accumulation, and activate UCP1. Therefore, food is a promising means for combating and treating diseases such as adiposity and comorbidities [142] (Fig. 7).

Resveratrol

Resveratrol is present mainly in grapes, berries, and other dietary constituents as a natural polyphenol [143]. It is a natural antioxidant that has preventive effects against hyperlipidemia, as well as cardiovascular and cerebrovascular diseases [144, 145]. Extensive research has conclusively shown that resveratrol significantly increases the heat production of BAT [146] and WAT browning [147] in rodents subjected to a high-food diet, which implies that resveratrol can combat obesity and improve various metabolic disorders. Moreover, the findings of researchers suggest that the impacts of resveratrol are likely attributable to the direct enhancement of UCP1 mRNA expression [148, 149]. For example, in Andrade JMO’s study [147], it was discovered that resveratrol could improve glycemic and lipid profiles by increasing UCP1 expression levels in mouse and human subcutaneous adipose tissue. Consistent with the above research, Hui et al. [150] proved that the ability of resveratrol to increase heat production might be partially driven by the gut microbiota; i.e., resveratrol can regulate bile acid metabolism by remodeling the gut microbiota, which mediates BAT activation and WAT browning by increasing UCP1 expression, which also suggests that although polyphenolic compounds are low in bioavailability, they can affect adipose tissue through the intestinal flora, thus achieving therapeutic effects. Moreover, p38 MAPK is necessary for resveratrol to stimulate the activation of UCP1, and resveratrol can counteract the LPV (an HIV protease inhibitor)-induced loss of UCP1 [151, 152, 154]. It is feasible to achieve precise control over UCP1 induction through the administration of resveratrol and LPV, suggesting promising applications in the development of safe antiobesity therapies.

Although animal experiments confirmed the protective effects of resveratrol against many diseases, including adiposity, reports of its toxicity and adverse effects after the consumption of resveratrol by humans have been reported, which may be related to the resveratrol doses used (the conversion of the effective dose used in animal experiments to the effective dose given to humans may be toxic to humans), the duration of resveratrol supplementation and the differences in the characteristics of the enrolled patients. Moreover, resveratrol can interact with some drugs, and these interactions can decrease the activities of these drugs [152,153,154]. Therefore, when the ability of resveratrol to promote an increase in UCP1 is investigated in the human body, a more uniform design of clinical trials is needed to investigate the effects of resveratrol properly and define its mechanisms of disease therapy and prevention.

Anthocyanins

Anthocyanins, another polyphenolic compound, are abundantly present in fruits and vegetables with dark hues, as are pigmented grains, such as berries, cherries, grapes, and purple onions [155]. Cyanidin-3-glucoside (C3G), a member of the anthocyanin family, has promising therapeutic implications for preventing and controlling obesity [156]. This is attributed to the ability of C3G to increase mitochondrial quantity and functionality, effectively modulating UCP1 transcription in both BAT and sWAT [157, 158]. Additionally, the UCP1 expression level can be notably increased by PRDM16, which results in preadipocyte differentiation into brown adipocytes. As in Han’s study [157], they reported that supplementation with C3G facilitates the upregulation of PRDM16. PRDM16 subsequently actively interacts with the promoter region of UCP1, which spans from − 500 to -150 base pairs, thereby stimulating its transcription. As a result, this process serves as a pivotal factor in facilitating the programming of BAT. Moreover, cell experiments have shown that C3G can facilitate the upregulation of UCP1 during early-phase supplementation [158]. However, anthocyanins, as polyphenolic compounds, also have the disadvantage of low bioavailability, ultimately limiting their potential clinical applications. Although new approaches, such as nanotechnology, can increase the bioaccessibility and bioavailability of anthocyanins, exploring alternative options might be more appropriate and economic.

Fucoxanthin

Fucoxanthin, the most abundant carotenoid, is commonly found in brown seaweeds and diatoms. Studies have demonstrated that fucoxanthin holds promise as a potential component for the management of adiposity [159, 160]. Fucoxanthin supplementation has been shown to reduce fat weight and adipocyte size effectively [161, 162]. In addition, by facilitating the elevation of UCP1, fucoxanthin can improve fatty acid β-oxidation activity and increase heat production and energy expenditure, which mediate the potential antiobesity effect of fucoxanthin [159, 163,164,165]. The standardized fucoxanthin powder, derived from Phaeodactylum extract (PE), contains fucoxanthin in amounts ranging from 0.035 to 0.06 (w/w). In a study conducted by Koo, the antiobesity properties of this novel standardized fucoxanthin powder were thoroughly evaluated in vitro and in vivo. The results indicated that PE exerts antiobesity effects by modulating lipid metabolism by suppressing PPARγ and enhancing UCP1 expression [164]. Andrea et al. [166] also researched the ability of PE to treat adiposity, and their discovery revealed that PE decreases the progression of adiposity in an animal model. This phenomenon is mediated by the accumulation of fucoxanthin metabolites in adipose tissues, facilitating the upregulation of UCP1 and heat production in iBAT and sWAT.

Furthermore, Nana et al. [167] conducted clinical trials to investigate the impact of fucoxanthin on obese Japanese adults. Although supplementation with fucoxanthin-enriched akamoku oil did not significantly affect visceral fat areas or resting energy expenditure, a noteworthy decrease in HbA1c levels was observed in the group receiving 2 mg/day fucoxanthin, particularly among individuals carrying the G/G alleles of the Ucp1 gene. Consistent with the findings of the other studies mentioned above, this report corroborates the existence of a correlation between fucoxanthin and the Ucp1 gene. However, further research involving a larger number of participants is necessary to establish more conclusive findings.

Unfortunately, although numerous brown seaweeds contain significant quantities of fucoxanthin, researchers have demonstrated that the bioavailability of fucoxanthin in humans is limited [168]. The combination of fucoxanthin with lipids, such as those in fish oil, may be effective. The enhanced antiobesity impact of fucoxanthin might be attributed to its solubility in fish oil, resulting in a better combination that effectively mitigates the weight of WAT by increasing UCP1 expression. Furthermore, extracting fucoxanthin at high concentrations from plants poses a significant challenge, and there are currently no economical methods available for producing fucoxanthin with a high degree of purity. This limitation restricts its further application, hence necessitating additional research efforts.

Tea catechins

Catechins are the most functional ingredients in tea. In terms of their different structures, catechins can be classified into six types: (-)- epigallocatechin gallate (EGCG), (-)-epicatechin gallate (ECG), (-)-epicatechin (EC), catechin (C), trace gallic acid (GA), and (-)- epigallocatechin (EGC). UCP1 mediates the efficacy of catechins in promoting heat production; thus, ameliorating obesity is widely acknowledged [169].

EGCG is the predominant polyphenol catechin detected in green tea. Studies have shown that EGCG has the potential to increase glucolipid metabolism in both mice and humans by suppressing adipogenesis, inducing WAT browning [170], and reducing plasma triglyceride levels [171]. Whether UCP1-related mechanisms/pathways contribute to lipid breakdown and whether EGCG exerts an effect on obesity reduction or browning of WAT in humans remain controversial. For example, Mi et al. [170] reported that EGCG can notably evoke the phosphorylation of AMPK and induce the browning of mature white adipocytes derived from iWAT preadipocytes by facilitating the upregulation of UCP1 and promoting mitochondrial biogenesis. Moreover, another study in 3T3-L1 cells revealed that EGCG supplementation promotes the upregulation of UCP1, accompanied by the downregulation of pivotal lipogenesis genes [172]. However, in another experiment, EGCG treatment did not facilitate the upregulation of UCP1 in BAT [173]. Furthermore, treatment with EGCG did not increase Ucp1 mRNA in human white adipocytes, and the application of EGCG did not reduce obesity, lipid breakdown, or browning of WAT [171]. Unlike EGCG, EGC, another type of catechin, was also proven to increase adiponectin and UCP1 transcription in mature adipocytes [174]. Therefore, there are indeed some challenges in translating animal data to human data, and more studies need to be performed on human subjects.

Capsaicin

Capsaicin is an agonist that acts on transient receptor potential vanilloid channel 1 (TRPV1). Through activation of TRPV1, capsaicin can activate metabolic modulators, including AMPK, PPAR-α, and UCP1 [175, 176], which indicates browning and thermogenesis. A subsequent study on two murine adipocyte models also demonstrated the potential of capsaicin for WAT browning. The application of capsaicin to 3T3-L1 and X9 cells contributes to a notable increase in brown fat-specific genes such as Ucp1, Prdm16, and Cidea [177]. Additionally, human dermal fibroblasts can directly convert into brown-like adipocytes after treatment with capsin [178]. This partially explains the mechanisms underlying the antiobesity effects of capsaicin.

Others

There are also numerous other phytochemicals that can enhance thermogenesis by upregulating UCP1 expression, such as hyperforin in Hypericum perforatum [179], nobiletin in citrus fruit [180, 181], sesamol in sesame seeds [182,183,184] and quercetin in onion peel [185].

The heat production induced by the diet represents a critical element in facilitating total energy expenditure, which is beneficial for preventing obesity. However, most of these experiments were performed in rodents and cells; there have been few clinical trials in this area, so comparative evidence in humans is minimal.

Pharmaceutical agents

HMG CoA reductase inhibitors: statins

Statins, which function as inhibitors of HMG-CoA reductase, are commonly utilized for managing blood lipid levels, treating hyperlipidemia, and preventing atherosclerosis, such as simvastatin, fluvastatin, and atorvastatin.

Researchers have demonstrated that simvastatin can facilitate the upregulation of UCP1, potentially ameliorating metabolic disorders (weight gain and dyslipidemia) [186]. However, the role of other statins in upregulating UCP1, inducing the browning of white adipocytes, and facilitating BAT activation remains controversial. Mauser [187] reported that treating brown adipocytes with atorvastatin did not result in any alteration in the protein expression of UCP1. Moreover, Balaz et al. [188] reported that fluvastatin facilitates the downregulation of the Ucp1 gene in human BAT. In other words, the application of statins is inversely correlated with the activity of human brown fat. These findings indicate that further investigation is necessary to elucidate the effects of statins on UCP1.

β3-Adrenoceptor agonists

β3-Adrenoceptor (β3-AR) is highly expressed in rodent adipocytes, especially in prototypical brown adipocytes, and activation of β3-AR in adipocytes can promote lipidolysis, thermogenesis, and weight loss [189, 190]. One possible explanation for this may be that stimulating β3-AR in mouse adipocytes triggers the activation of UCP1, which results in increased heat generation [191, 192]. Norepinephrine (NE) binds to BAT β3-AR, triggering internal signaling pathways that result in elevated UCP1 levels and the lipolysis of triglycerides into free fatty acids, which subsequently trigger UCP1 located on the inner mitochondrial membrane.

CL316243 is an effective and selective β3-AR agonist in rodents [193]. Supplementation with CL316,243 can result in notable remodeling of WAT, which is marked by increased UCP1 expression and multilocular adipocytes. For example, Masoud Ghorbani [194] demonstrated that administering CL316,243 to both lean and obese Zucker rats resulted in significant restructuring of WAT, which possesses the characteristics mentioned above, preferentially in lean rats. However, its application in humans may be impeded by its limited efficacy, even for the cloned human β3-AR, and it has poor bioavailability, which also prevents its use in humans, possibly because human brown adipocytes lack β3-AR or have low expression levels of β3-AR. Furthermore, the use of this medication has led to notable adverse effects on the cardiovascular system, including hypertension and tachycardia [195].

Fortunately, mirabegron has numerous favorable metabolic properties in response to CL316243. It is a secure, dynamic β3-AR agonist known for its clinical application in treating overactive bladders. Recent preclinical studies [196, 197] conducted on adult humans have indicated the potential of mirabegron to increase the metabolic rate in human BAT, which suggests that mirabegron may be a favorable strategy to ameliorate metabolic disorders. Moreover, Dehvari’s research [198] demonstrated that mirabegron has a direct effect on adipocytes through β3-AR, resulting in increased levels of glucose absorption, UCP1 mRNA, and OCR (oxygen consumption rate). Additionally, UCP1, an essential thermogenic protein in adipose tissues, is indispensable for the influence of mirabegron on glucose tolerance in vivo and may be one of the targets or mechanisms for its antiobesity/diabetes effects.

However, whether β3-ARs mediate thermogenesis in humans and whether mirabegrons, as β3-AR agonists, mediate thermogenesis in human adipose tissue are controversial. In Cheryl’s study [199], when the expression of β3-AR was silenced, the stimulatory effects of mirabegron, a specific agonist of human β3-AR, on lipolysis and heat production were abrogated. These findings indicate that β3-ARs are necessary for maintaining lipolysis and facilitating heat generation in human adipocytes. However, Denis P et al. [195] demonstrated that the therapeutic dosage of mirabegron (50 mg) does not induce thermogenesis in human brown adipose tissue. They confirmed that β2-AR, rather than β3-AR, serves as the primary target for pharmacologically activating brown adipocytes. Human brown adipocytes lack the β3-AR receptor, thus rendering them unresponsive to mirabegron in vitro. Therefore, differences in gene expression might exist between brown adipocytes differentiated in vitro and those directly analyzed from biopsied tissue.

The PPAR agonist

Peroxisome proliferator-activated receptor (PPAR) agonists are attracting considerable interest as promising therapeutic options in MASLD and NASH research [200]. Pioglitazone and rosiglitazone, both antidiabetic drugs and PPARγ agonists, have been demonstrated to facilitate UCP1 upregulation in BAT and WAT [201]. Research by Merlin et al. [191] revealed that treating adipocytes with rosiglitazone can facilitate UCP1 upregulation and enhance mitochondrial function, particularly in brown and inguinal white adipocytes.

Moreover, studies [42, 201] have shown that pioglitazone can increase UCP1 gene expression in mouse BAT. In particular, the combined application of pioglitazone and cold acclimation exhibited a synergistic effect, resulting in a notable increase in the overall abundance of UCP1 and thermogenesis-related proteins (PGC-1α and CIDEA) in iBAT and iWAT compared with cold exposure or pioglitazone treatment alone [42]. Moreover, pioglitazone treatment effectively enhances glucose uptake and protects iWAT from the mass reduction caused by cold.

Additionally, oleoyl ethanolamide (OEA), which serves as an agonist of PPAR-α, has garnered considerable attention recently. Compared with placebo, OEA is involved in various unique homeostatic functions, including regulating appetite and dietary intake, stimulating lipolysis, and promoting fatty acid oxidation, and scholars [202] reported that OEA supplementation can significantly facilitate the upregulation of PPAR-α and UCP1 in the peripheral blood mononuclear cells of humans with adiposity.

Finally, although PPAR agonists are effective treatments for metabolic diseases, including the potential to increase UCP1 to attenuate adiposity, we must consider the safety of the PPAR agonists. The side effects of PPAR-γ agonists are weight gain, fluid retention, and increased risk of congestive heart failure and bone fractures. Rosiglitazone increases risk of Myocardial infarction. The long-term use of pioglitazone is possibly associated with an increased risk of incident bladder cancer [203].

TRPM8 agonists—Menthol and Icilin

TRPM8 functions as the principal cold receptor within the peripheral nervous system of mice [204]. TRPM8, which is expressed in brown, brite, and white adipocytes [205, 206], is activated by chemical cooling agents, such as menthol, or when the surrounding temperature falls below approximately 26 °C, indicating its role in facilitating the recognition of cold thermal stimuli by primary sensory neurons [207]. Activation of the TRPM8 channel stimulates thermogenesis, which relies on UCP1 and acts as a protective measure against adiposity [208].

Icilin is a synthetic TRPM8 agonist. Similarly, Rossato et al. reported that treating human white adipocytes with Sicilian can significantly increase basal and insulin-induced glucose uptake and induce UCP1 expression [205]. Menthol, a natural compound derived from mint plants, serves as a TRPM8 agonist, effectively activating both TRPM8 and UCP1 in adipose tissue and subsequently promoting thermogenesis, underscoring its potential role in regulating body temperature [121].

Inhibitors of COX-2

COX-2 can facilitate lipid metabolism. Celecoxib, which serves as an inhibitor of COX-2, can lower the expression of UCP1 and COX-2 in a burn injury model and subsequently attenuate burn injury-induced hypermetabolism [209].

GSK3 inhibitor

Lithium, a widely recognized inhibitor of GSK3, is frequently prescribed for the management of bipolar disorder. Clinically, high doses of lithium supplements can increase the risk of obesity. Nevertheless, studies have shown that low doses of lithium supplements can reduce obesity and atherosclerosis [210]. For example, Fajardo et al. reported a negative correlation between trace amounts of naturally occurring lithium in water and the incidence of obesity, which is attributed, at least in part, to the inhibitory effects of lithium on GSK3 and the increase in UCP1 content in adipocytes [211, 212]. Moreover, when lithium is used at a relatively high dose (450–1500 mg) and taken for a long time, it can produce side effects, especially when combined with the administration of risperidone [213].

Other drugs

Qiu et al. [214] established a UCP1-2 A-GFP reporter mouse model, enabling the utilization of GFP intensity as a surrogate marker for the UCP1 protein. Subsequently, they embarked on a search for FDA-approved medications that possess the ability to stimulate endogenous UCP1 expression in adipocytes and discovered that Sutent could increase UCP1 levels in brown fat cells. In addition, the administration of Sutent resulted in the upregulation of various genes involved in thermogenesis or brown adipocyte differentiation, including PGC-1α and PRDM16. Consequently, weight was reduced through increased thermogenic activity and metabolism. Using this model, they reported that glyburid also has the potential to reduce UCP1 [215].

Glyburide is a medication commonly prescribed to effectively reduce blood glucose levels and manage type 2 diabetes. Qiu et al. [214] revealed that glyburide supplementation markedly facilitates the elevation of UCP1 in fat tissue. Furthermore, the direct injection of glyburide into the inguinal WAT resulted in substantial upregulation of UCP1 expression and thermogenic activity.

Notably, certain medications, such as melatonin, inhibit UCP1 expression to achieve therapeutic outcomes [216]. In other words, we should also note that in specific disease states, we need to inhibit the activity of UCP1, such as burns, sepsis, and cancer cachexia (See Table 2).

Table 2 Pharmaceutical agents

Full size table

The gut microbiota

The gut microbiota has coevolved with its hosts over time, forming an integral and indispensable component of the human body’s ecosystem. Known as the “microbiome,” the collective genetic material encoded by these microorganisms exceeds the human genome by a staggering 150-fold [217]; it performs some essential functions of the human body. Moreover, the microbiota is often intricately linked with the treatment and management of numerous diseases, including adiposity and MASLD. The microbiota promotes thermogenesis by influencing WAT browning, which may be one of the underlying mechanisms [218].

As Moreno et al. [218] demonstrated, the relative abundance of Firmicutes is positively correlated with UCP1 in sWAT. In other words, a connection exists between the gut microbiota composition and WAT browning. Moreover, Li et al. reported that diminishing the microbiota of mice with antibiotics results in a reduction in UCP1. This, in turn, suppresses the browning process of WAT and damages the heat production potential of BAT [219], which suggests that the gut microbiota directly impacts the thermogenesis of UCP1.

In addition, many other probiotics can activate UCP1 in adipose tissue. As a potential probiotic, Parabacteroides distasonis can interact with bile acids (gut microbiota-bile acid crosstalk), mediate the activation of UCP1, and promote an increase in glucose and lipid metabolism. Consequently, the administration of probiotics can control rapid postcaloric restriction (CR) weight gain [220].

Lactobacillus plantarum, a probiotic group of the human gastrointestinal tract, is widely distributed and commonly found in fermented vegetables and fruit juices. Lactobacillus plantarum has various functions, including preserving the equilibrium of the gut microbiota, enhancing the immune system, and facilitating nutrient absorption. According to the research of Gus et al. [221], Lactobacillus plantarum dy-1 (LFBE) mitigates obesity by upregulating UCP1 expression in the fat tissue of an HFD-fed animal model. Moreover, fermented barley extract with LFBE can also ameliorate HFD-induced obesity by triggering BAT activation and WAT browning. However, microbiota that damage thermogenesis genes, such as UCP1, also exist. Porphyromonas gingivalis (P. gingivalis) is a type of bacteria that can cause periodontal disease. In addition, periodontal bacteria, such as P. gingivalis, can migrate and settle in the gut through oral administration [222]. Thus, periodontal bacteria may result in systemic diseases, including obesity. Zheng et al. [223] reported that P. gingivalis can reduce UCP1 expression in the BAT of mice; these negative influences on BAT are attributed to the lipopolysaccharide (LPS) component of P. gingivalis, providing a plausible explanation for how periodontal disease facilitates the development of adiposity.

The gut microbiota, which serves as a metabolic “organ,” can contribute to thermogenesis by generating abundant metabolites, which act as ligands to activate thermogenic pathways. Dietary bile acids (BAs) can repress HFD-induced adiposity through increased energy expenditure mediated by the thermogenesis gene UCP1 [224]. In other words, BAs, such as CDCA and LCA, can regulate UCP1 expression in adipose tissue. Han et al. demonstrated that curcumin can modulate BA metabolism by restructuring the gut microbiota, which results in increased fractions of circulating DCA and LCA, thereby increasing UCP1-dependent thermogenesis [225]. Wang et al. [220] reported that treatment with Parabacteroides distasonis primarily elevated the concentrations of unconjugated non-12OH BAs, UDCA, and LCA. These bile acids function as agonists to trigger UCP1 signaling pathways and increase energy metabolism. Moreover, in Crohn et al.’s disease, microorganisms and metabolites (succinate) can translocate to the surrounding adipose tissue due to gut barrier defects, which then promote WAT browning [226].

In summary, the gut microbiota and its metabolites can facilitate heat production through their interactions with UCP1. On the other hand, UCP1 can also reshape the gut microbiota through the adipose-liver-gut axis and contribute to decreased fat accumulation [227]. This may constitute a bidirectional regulatory system that can be exploited (Fig. 8).

The strengths and limitations of this review

The primary purpose of scientific research and theoretical exploration is to better serve clinical practice and patients. In this review, we summarize the thermogenic stimuli that have activated UCP1 in recent decades, including physical and environmental factors (cold stimulation and exercise) and factors related to traditional Chinese medicine. The summarization of these UCP1 stimuli provides clinical doctors with valuable guidance for the use of clinical drugs and helps them gain better insights into the treatment of metabolic diseases, such as adiposity and MASLD. In particular, we have summarized the nonpharmacological factors that have the potential to stimulate UCP1 activation, including physical exercise and acupuncture, which may be safer options for treating metabolic diseases. Moreover, for the first time, we summarize the factors of traditional Chinese medicine that can stimulate UCP1 activation, providing new insights for disease treatment. Hopefully, this review will provide valuable guidance for treating clinical diseases and using clinical drugs.

Nevertheless, there are certain limitations. First, although the factors related to traditional Chinese medicine that can stimulate the activation of UCP1 have been summarized, the underlying theory of traditional Chinese medicine as to why these factors stimulate the activation of UCP1 and enhance adipose tissue thermogenesis has yet to be clarified thoroughly. Additionally, the summarization of factors that stimulate UCP1 activation is limited, and not all factors are fully understood.

Conclusion and future perspectives

Facilitating the enhancement of heat production and energy expenditure is an effective way to improve and treat numerous diseases, including adiposity and MASLD. UCP1, whose expression is restricted to brown and beige adipocytes in humans and rodents, is a critical target for facilitating heat production in adipose tissue. Cold exposure, physical exercise, acupuncture, Chinese herbal formulas, pharmacological agents, food ingredients, gut microbiota, and pharmaceutical agents are commonly associated with the activation and elevation of UCP1 in BAT and WAT.

Among the various activators that trigger thermogenesis, ambient cold exposure is the first factor discovered to activate this process. Exposure to ambient cold markedly stimulates the SNS, which subsequently triggers β2-AR- and β3-AR-mediated nonshivering thermogenesis in humans and rodents, respectively [195, 228]. Unfortunately, cold exposure can only cause initial, strong, but short, nonselective browning of most adipocytes in rpWAT; a few adipocytes maintain brown-like characteristics in the long run [35]. In addition, exercise, as a noninvasive and tolerable physical alternative, benefits various organ systems in mammals and humans. Physical exercise is an excellent means for initiating the browning process, partly because it stimulates irisin gene expression, mitigates hypothalamic inflammation, and increases the expression of the POMC neuron gene [65]. These changes, in turn, promote the expression of the thermogenesis gene UCP1 [56, 63]. Moreover, owing to their multicomponent and multitarget advantages, traditional Chinese medicine therapies, such as acupuncture, Chinese herbal formulas, medicinal herbs, and their bioactive compounds, can also activate UCP1 and increase adipose tissue thermogenesis. With the spread and development of Chinese medicine worldwide, an increasing number of people will benefit from its prominent effects and few side effects. Furthermore, many functional foods and food ingredients have the potential to activate UCP1 and promote thermogenesis in adipose tissue, which provides more reliable ways to manage diseases and maintain health. The pharmacological activation of UCP1, such as statins, mirabegron, pioglitazone, and rosiglitazone, has gradually increased. Furthermore, there is a strong connection between the gut microbiota and the activation of UCP1. In other words, UCP1 activation can be achieved through a diverse array of methods.

From the preceding discussion, it becomes evident that UCP1 is pivotal in enhancing the heat production of adipose tissue and that activating UCP1 is an excellent way to treat obesity-related metabolic diseases, including MASLD. Most researchers are also committed to studying the agonists of UCP1. However, several crucial points deserve the utmost attention.

First, while BAT represents a minor percentage of the total adipose tissue mass, its activation can significantly increase overall oxygen consumption [229]. The powerful capacity of BAT as a target for ameliorating obesity appears encouraging. For example, Valdivia reported that although drug therapy and cold exposure can increase the UCP1 content in WAT, it only accounts for a small part (approximately 20%) of the total UCP1 content in BAT. These findings underscore the significant role of iBAT in thermogenesis compared with that of iWAT [42]. Furthermore, when the mice were fed under conditions mimicking human thermal and nutritional environments, the morphological, cellular, and molecular features of classical BAT, but not beige adipose tissue, closely resembled those of human BAT. Interestingly, only classical BAT physiologically humanized mice possess high thermogenic potential [230]. In other words, even under thermoneutrality conditions, BAT maintains its characteristic brown-like physiological properties despite being masked by a white-like morphology [33]. Therefore, when promoting the UCP1 activation in BAT, more excellent heat production will be achieved.

Second, most experimental animals are raised under standard animal housing conditions (“standard” mice). Despite the strong anatomical resemblance between brown fat deposits (for example, supraclavicular depots) in mice and humans [231], there are morphological and molecular distinctions between human and rodent BAT [230]. Importantly, if experimental animals are raised in circumstances involving human thermal and nutritional conditions (“physiologically humanized” mice), they exhibit different gene expression patterns than “standard” mice do, and their BAT phenotype is also humanized [232]. Therefore, when we evaluate the heat production capacity of fat tissue, maintaining the mice under appropriate conditions may improve the experimental conditions and increase the compatibility of the results with humans, which can better clarify the functions of the drugs. In addition, we need to conduct more clinical experiments in the future because animal experiments cannot fully explain the pathological changes in humans.

Third, much evidence proves that UCP1-independent thermogenic pathways also contribute to the body’s heat production and the regulation of whole-body energy homeostasis [233, 234], such as creatine kinase b (CKB) [235], transcription factor 4 (ATF4) [236] in brown adipocytes and sarco/endoplasmic reticulum Ca2+-ATPase2b (SERCA2b)-mediated calcium cycling [237] in beige adipocytes. As the study by Rahbani JF et al. suggested, thermogenic adipocytes utilize nonparalogous protein redundancy through UCP1 and CKB to promote cold-induced energy dissipation. These mechanisms have the potential to supplement or even replace UCP1-driven thermogenesis. UCP1-independent thermogenesis enhances overall energy metabolism, which helps improve conditions such as glucose and lipid metabolism disorders, especially in specific individuals, such as aged individuals and those lacking UCP1-positive adipocytes [238]. Therefore, these mechanisms must also be treated with the utmost severity.

Fourth, we can also obtain corresponding pharmacological effects by inhibiting the activity of UCP1 in specific states of diseases, such as burns, sepsis, and cancer cachexia [239]. Specifically, the catabolism of stored nutrients can be reduced by decreasing the expression of UCP1 to slow uncontrolled metabolism in disease states. Experimental studies [240, 241] have definitively demonstrated that decreasing the expression level of UCP1 and lowering heat production are beneficial for alleviating the pathological state of cachexia. As proposed by Cheung [242], supplementation with vitamin D could diminish the increased expression of UCP1 in beige adipose cells, thereby mitigating adipose tissue browning and consequently enhancing overall quality of life. The extracts of Arctium lappa L. Fruit (Arctii Fructus) [241], Astragalus polysaccharide [240], and the functional food SiBaoChongCao isolated from Cordyceps sinensis [243] also have the potential to attenuate the browning of WAT through UCP1. Moreover, these agents help maintain the equilibrium between whitening and browning of adipocytes and are beneficial for the development of safe therapies [151]. Therefore, exploring UCP1 inhibitors to suppress UCP1 expression and heat production may be necessary. In other words, it is equally important to research UCP1 inhibitors and UCP1 agonists.

Finally, although experimental research indicates that commonly used clinical drugs can activate UCP1 and promote heat production in adipose tissue, their primary function is not to stimulate heat production. Therefore, the use of those medications to activate UCP1 should be comprehensively considered. For example, mirabegron, a β3-adrenoceptor agonist, has been shown to upregulate UCP1, but its primary use is for overactive bladder syndrome (urgency, nocturia). The use of mirabegron is perfect and correct only when increased heat production and the treatment of overactive bladder syndrome are both required by patients. Moreover, the side effects of pharmaceuticals, such as PPAR agonists, should be considered. In addition, although animal experiments confirmed that food and food ingredients can activate UCP1, few clinical trials have investigated this topic. The conversion of the effective dose used in animal experiments to the effective dose given to humans may be toxic to humans, and how much food should we eat to reach an effective dose? These are the challenges that need to be addressed in the future.

Moreover, UCP1 activation may be a double-edged sword. The increased heat production caused by the activation of UCP1 may not be beneficial for specific diseases, such as burns, sepsis, and cancer cachexia. Therefore, clinicians should consider whether the increased heat production caused by certain medications, physical therapies, and diets could be disadvantageous factors in treating these diseases.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

UCP1:: Uncoupling protein 1
POMC:: Proopiomelanocortin
SNS:: Sympathetic nervous system
ACE:: Acupoint catgut embedding
MASLD:: Metabolic dysfunction-associated steatotic liver disease
FNDC5:: Fibronectin type III domain containing 5
AA:: Auricular acupuncture
END:: Constant–moderate endurance training
TRPV1:: Random receptor potential vanilloid channel 1
BAT:: Brown adipose tissue
GLP-1:: Glucagon-like peptide 1
PGC-1α:: PPAR-γ coactivator-1α
Cidea:: Cell death-inducing DNA fragmentation factor A-like effector A
iBAT:: Interscapular BAT
eWAT:: Epididymis WAT
iWAT:: Inguinal WAT
sWAT:: Subcutaneous WAT
rWAT:: Retroperitoneal WAT
CNS:: Central nervous system
PRDM16:: PR domain containing 16
β-END:: β-endorphin
MOTS-c:: Mitochondrial open reading frame
HFD:: High-fat diet
CA:: Catecholamine
WAT:: White adipose tissue
PKA:: Protein kinase A
AR:: Adrenoreceptors
TRPM8:: Transient receptor potential (TRP) cation channel subfamily M member 8
AET:: Aerobic exercise training; PPARα, nuclear hormone receptor peroxisome proliferator-activated

References

Powell-Wiley TM, Poirier P, Burke LE, Després JP, Gordon-Larsen P, Lavie CJ, et al. Obesity and Cardiovascular Disease: A Scientific Statement from the American Heart Association. Circulation. 2021;143(21):e984–1010.
Article PubMed PubMed Central Google Scholar
Guerra C, Koza RA, Yamashita H, Walsh K, Kozak LP. Emergence of brown adipocytes in white fat in mice is under genetic control. Effects on body weight and adiposity. J Clin Invest. 1998;102(2):412–20.
Article CAS PubMed PubMed Central Google Scholar
Wu J, Boström P, Sparks LM, Ye L, Choi JH, Giang AH, et al. Beige adipocytes are a distinct type of thermogenic fat cell in mouse and human. Cell. 2012;150(2):366–76.
Article CAS PubMed PubMed Central Google Scholar
Ikeda K, Maretich P, Kajimura S. The common and distinct features of Brown and Beige adipocytes. Trends Endocrinol Metab. 2018;29(3):191–200.
Article CAS PubMed PubMed Central Google Scholar
Mascha Koenen MA, Hill P, Cohen JR, Sowers. Obesity, adipose tissue and vascular dysfunction. Circul Res. 2021;128(7):951–68.
Article Google Scholar
Shingo Kajimura BM, Spiegelman, Seale P. Brown and beige fat: physiological roles beyond heat generation. Cell Metabol. 2015;22(4):546–59.
Article Google Scholar
Edward T, Chouchani L, Kazak, Bruce M, Spiegelman. New advances in adaptive thermogenesis: Ucp1 and beyond. Cell Metabol. 2019;29(1):27–37.
Article Google Scholar
Yongguo Li and Tobias Fromme. Uncoupling protein 1 does not produce heat without activation. Int J Mol Sci. 2022;23(5):2406.
Article PubMed Google Scholar
Saito M, Yoneshiro T, Matsushita M. Activation and recruitment of brown adipose tissue by cold exposure and food ingredients in humans. Best Pract Res Clin Endocrinol Metab. 2016;30(4):537–47.
Article CAS PubMed Google Scholar
Cypess AM, Haft CR, Laughlin MR, Hu HH. Brown fat in humans: consensus points and experimental guidelines. Cell Metab. 2014;20(3):408–15.
Article CAS PubMed PubMed Central Google Scholar
van Marken Lichtenbelt WD, Vanhommerig JW, Smulders NM, Drossaerts JM, Kemerink GJ, Bouvy ND, et al. Cold-activated brown adipose tissue in healthy men. N Engl J Med. 2009;360(15):1500–8.
Article PubMed Google Scholar
Zingaretti MC, Crosta F, Vitali A, Guerrieri M, Frontini A, Cannon B, et al. The presence of UCP1 demonstrates that metabolically active adipose tissue in the neck of adult humans truly represents brown adipose tissue. FASEB J. 2009;23(9):3113–20.
Article CAS PubMed Google Scholar
Lidell ME, Betz MJ, Dahlqvist Leinhard O, Heglind M, Elander L, Slawik M, et al. Evidence for two types of brown adipose tissue in humans. Nat Med. 2013;19(5):631–4.
Article CAS PubMed Google Scholar
Virtanen KA, Lidell ME, Orava J, Heglind M, Westergren R, Niemi T, et al. Functional brown adipose tissue in healthy adults. N Engl J Med. 2009;360(15):1518–25.
Article CAS PubMed Google Scholar
Kalinovich AV, de Jong JM, Cannon B, Nedergaard J. UCP1 in adipose tissues: two steps to full browning. Biochimie. 2017;134:127–37.
Article CAS PubMed Google Scholar
Ledesma A, de Lacoba MG, Rial E. The mitochondrial uncoupling proteins. Genome Biol. 2002;3(12):REVIEWS3015.
Article PubMed PubMed Central Google Scholar
Klingenberg M, Echtay KS, Bienengraeber M, Winkler E, Huang SG. Structure-function relationship in UCP1. Int J Obes Relat Metab Disord. 1999;23(Suppl 6):S24–9.
Article CAS PubMed Google Scholar
Ricquier D, Bouillaud F. The uncoupling protein homologues: UCP1, UCP2, UCP3, StUCP and AtUCP. Biochem J. 2000;345(Pt 2):161–79.
Article CAS PubMed PubMed Central Google Scholar
Monteiro BS, Freire-Brito L, Carrageta DF, Oliveira PF, Alves MG. Mitochondrial uncoupling proteins (UCPs) as key modulators of ROS Homeostasis: a crosstalk between Diabesity and male infertility? Antioxid (Basel). 2021;10(11):1746.
Article CAS Google Scholar
Ruprecht JJ, Kunji ERS. Structural Mechanism of Transport of Mitochondrial Carriers. Annu Rev Biochem. 2021;90:535–58.
Article CAS PubMed Google Scholar
Hass DT, Barnstable CJ. Uncoupling proteins in the mitochondrial defense against oxidative stress. Prog Retin Eye Res. 2021;83:100941.
Article CAS PubMed PubMed Central Google Scholar
Kang Y, Chen L. Structural basis for the binding of DNP and purine nucleotides onto UCP1. Nature. 2023;620(7972):226–31.
Article CAS PubMed Google Scholar
Nicholls DG, Bernson VS, Heaton GM. The identification of the component in the inner membrane of brown adipose tissue mitochondria responsible for regulating energy dissipation. Experientia Suppl. 1978;32:89–93.
Article CAS PubMed Google Scholar
Hoang T, Smith MD, Jelokhani-Niaraki M. Expression, folding, and proton transport activity of human uncoupling protein-1 (UCP1) in lipid membranes: evidence for associated functional forms. J Biol Chem. 2013;288(51):36244–58.
Article CAS PubMed PubMed Central Google Scholar
Ježek P, Jabůrek M, Porter RK. Uncoupling mechanism and redox regulation of mitochondrial uncoupling protein 1 (UCP1). Biochim Biophys Acta Bioenerg. 2019;1860(3):259–69.
Article PubMed Google Scholar
Inokuma K, Ogura-Okamatsu Y, Toda C, Kimura K, Yamashita H, Saito M. Uncoupling protein 1 is necessary for norepinephrine-induced glucose utilization in brown adipose tissue. Diabetes. 2005;54(5):1385–91.
Article CAS PubMed Google Scholar
Fedorenko A, Lishko PV, Kirichok Y. Mechanism of fatty-acid-dependent UCP1 uncoupling in brown fat mitochondria. Cell. 2012;151(2):400–13.
Article CAS PubMed PubMed Central Google Scholar
Chernogubova E, Hutchinson DS, Nedergaard J, Bengtsson T. Alpha1- and beta1-adrenoceptor signaling fully compensates for beta3-adrenoceptor deficiency in brown adipocyte norepinephrine-stimulated glucose uptake. Endocrinology. 2005;146(5):2271–84.
Article CAS PubMed Google Scholar
Zheng Q, Lin J, Huang J, Zhang H, Zhang R, Zhang X, et al. Reconstitution of UCP1 using CRISPR/Cas9 in the white adipose tissue of pigs decreases fat deposition and improves thermogenic capacity. Proc Natl Acad Sci U S A. 2017;114(45):E9474–82.
Article CAS PubMed PubMed Central Google Scholar
Klein Hazebroek M, Laterveer R, Kutschke M, Ramšak Marčeta V, Barthem CS, Keipert S. Hyperphagia of female UCP1-deficient mice blunts anti-obesity effects of FGF21. Sci Rep. 2023;13(1):10288.
Article CAS PubMed PubMed Central Google Scholar
Maurer SF, Fromme T, Grossman LI, Hüttemann M, Klingenspor M. The brown and brite adipocyte marker Cox7a1 is not required for non-shivering thermogenesis in mice. Sci Rep. 2015;5:17704.
Article CAS PubMed PubMed Central Google Scholar
Dieckmann S, Strohmeyer A, Willershäuser M, Maurer SF, Wurst W, Marschall S, et al. Susceptibility to diet-induced obesity at thermoneutral conditions is independent of UCP1. Am J Physiol Endocrinol Metab. 2022;322(2):E85–100.
Article CAS PubMed Google Scholar
Moser C, Straub LG, Rachamin Y, Dapito DH, Kulenkampff E, Ding L, et al. Quantification of adipocyte numbers following adipose tissue remodeling. Cell Rep. 2021;35(4):109023.
Article CAS PubMed Google Scholar
Cypess AM, Chen YC, Sze C, Wang K, English J, Chan O, et al. Cold but not sympathomimetics activates human brown adipose tissue in vivo. Proc Natl Acad Sci U S A. 2012;109(25):10001–5.
Article CAS PubMed PubMed Central Google Scholar
Jankovic A, Golic I, Markelic M, Stancic A, Otasevic V, Buzadzic B, et al. Two key temporally distinguishable molecular and cellular components of white adipose tissue browning during cold acclimation. J Physiol. 2015;593(15):3267–80.
Article CAS PubMed PubMed Central Google Scholar
Waldén TB, Hansen IR, Timmons JA, Cannon B, Nedergaard J. Recruited vs. nonrecruited molecular signatures of brown, brite, and white adipose tissues. Am J Physiol Endocrinol Metab. 2012;302(1):E19–31.
Article PubMed Google Scholar
Nedergaard J, Cannon B. The browning of white adipose tissue: some burning issues. Cell Metab. 2014;20(3):396–407.
Article CAS PubMed Google Scholar
Okamatsu-Ogura Y, Kuroda M, Tsutsumi R, Tsubota A, Saito M, Kimura K, et al. UCP1-dependent and UCP1-independent metabolic changes induced by acute cold exposure in brown adipose tissue of mice. Metabolism. 2020;113:154396.
Article CAS PubMed Google Scholar
Sepa-Kishi DM, Jani S, Da Eira D, Ceddia RB. Cold acclimation enhances UCP1 content, lipolysis, and triacylglycerol resynthesis, but not mitochondrial uncoupling and fat oxidation, in rat white adipocytes. Am J Physiol Cell Physiol. 2019;316(3):C365–76.
Article CAS PubMed PubMed Central Google Scholar
Shi M, Huang XY, Ren XY, Wei XY, Ma Y, Lin ZZ, et al. AIDA directly connects sympathetic innervation to adaptive thermogenesis by UCP1. Nat Cell Biol. 2021;23(3):268–77.
Article CAS PubMed Google Scholar
Divakaruni AS, Humphrey DM, Brand MD. Fatty acids change the conformation of uncoupling protein 1 (UCP1). J Biol Chem. 2012;287(44):36845–53.
Article CAS PubMed PubMed Central Google Scholar
Valdivia LFG, Castro É, Eichler RADS, Moreno MF, de Sousa É, Jardim GFR, et al. Cold acclimation and pioglitazone combined increase thermogenic capacity of brown and white adipose tissues but this does not translate into higher energy expenditure in mice. Am J Physiol Endocrinol Metab. 2023;324(4):E358–73.
Article CAS PubMed Google Scholar
McKie GL, Medak KD, Shamshoum H, Wright DC. Topical application of the pharmacological cold mimetic menthol stimulates brown adipose tissue thermogenesis through a TRPM8, UCP1, and norepinephrine dependent mechanism in mice housed at thermoneutrality. FASEB J. 2022;36(3):e22205.
Article CAS PubMed Google Scholar
Dong M, Yang X, Lim S, Cao Z, Honek J, Lu H, et al. Cold exposure promotes atherosclerotic plaque growth and instability via UCP1-dependent lipolysis. Cell Metab. 2013;18(1):118–29.
Article CAS PubMed PubMed Central Google Scholar
Symonds ME, Farhat G, Aldiss P, Pope M, Budge H. Brown adipose tissue and glucose homeostasis-the link between climate change and the global rise in obesity and diabetes. Adipocyte. 2019;8(1):46–50.
Article CAS PubMed Google Scholar
Symonds ME, Pope M, Bloor I, Law J, Alagal R, Budge H. Adipose tissue growth and development: the modulating role of ambient temperature. J Endocrinol. 2021;248(1):R19–28.
Article CAS PubMed Google Scholar
Alizadeh Pahlavani H. Possible roles of exercise and apelin against pregnancy complications. Front Endocrinol (Lausanne). 2022;13:965167.
Article PubMed Google Scholar
Swift DL, McGee JE, Earnest CP, Carlisle E, Nygard M, Johannsen NM. The effects of Exercise and physical activity on weight loss and maintenance. Prog Cardiovasc Dis. 2018;61(2):206–13.
Article PubMed Google Scholar
Takaishi K, Oshima T, Eto H, Nishihira M, Nguyen ST, Ochi R, et al. Impact of Exercise and Detraining during Childhood on Brown Adipose tissue whitening in obesity. Metabolites. 2021;11(10):677.
Article CAS PubMed PubMed Central Google Scholar
Keating SE, Johnson NA, Mielke GI, Coombes JS. A systematic review and meta-analysis of interval training versus moderate-intensity continuous training on body adiposity. Obes Rev. 2017;18(8):943–64.
Article CAS PubMed Google Scholar
Wewege M, van den Berg R, Ward RE, Keech A. The effects of high-intensity interval training vs. moderate-intensity continuous training on body composition in overweight and obese adults: a systematic review and meta-analysis. Obes Rev. 2017;18(6):635–46.
Article CAS PubMed Google Scholar
Ramos JS, Dalleck LC, Tjonna AE, Beetham KS, Coombes JS. The impact of high-intensity interval training versus moderate-intensity continuous training on vascular function: a systematic review and meta-analysis. Sports Med. 2015;45(5):679–92.
Article PubMed Google Scholar
Martinez-Huenchullan SF, Ban LA, Olaya-Agudo LF, Maharjan BR, Williams PF, Tam CS, et al. Constant-moderate and high-intensity interval Training have Differential benefits on Insulin Sensitive Tissues in High-Fat Fed Mice. Front Physiol. 2019;10:459.
Article PubMed PubMed Central Google Scholar
Kim S, Park DH, Lee SH, Kwak HB, Kang JH. Contribution of high-intensity interval Exercise in the fasted state to Fat Browning: potential roles of Lactate and β-Hydroxybutyrate. Med Sci Sports Exerc. 2023;55(7):1160–71.
Article CAS PubMed PubMed Central Google Scholar
Weltman A, Wood CM, Womack CJ, Davis SE, Blumer JL, Alvarez J, et al. Catecholamine and blood lactate responses to incremental rowing and running exercise. J Appl Physiol (1985). 1994;76(3):1144–9.
Article CAS PubMed Google Scholar
Cho E, Jeong DY, Kim JG, Lee S. The Acute effects of Swimming Exercise on PGC-1α-FNDC5/Irisin-UCP1 expression in male C57BL/6J mice. Metabolites. 2021;11(2):111.
Article CAS PubMed PubMed Central Google Scholar
Picoli CC, Gilio GR, Henriques F, Leal LG, Besson JC, Lopes MA, et al. Resistance exercise training induces subcutaneous and visceral adipose tissue browning in Swiss mice. J Appl Physiol (1985). 2020;129(1):66–74.
Article PubMed Google Scholar
Liu Y, Guo C, Liu S, Zhang S, Mao Y, Fang L. Eight weeks of high-intensity interval static strength training improves skeletal muscle atrophy and motor function in aged rats via the PGC-1α/FNDC5/UCP1 pathway. Clin Interv Aging. 2021;16:811–21.
Article CAS PubMed PubMed Central Google Scholar
Ringholm S, Grunnet Knudsen J, Leick L, Lundgaard A, Munk Nielsen M, Pilegaard H. PGC-1α is required for exercise and exercise training-induced UCP1 up-regulation in mouse white adipose tissue. PLoS ONE. 2013;8(5):e64123.
Article PubMed PubMed Central Google Scholar
Karadedeli MS, Schreckenberg R, Kutsche HS, Schlüter KD. Effects of voluntary exercise on the expression of browning markers in visceral and subcutaneous fat tissue of normotensive and spontaneously hypertensive rats. Pflugers Arch. 2022;474(2):205–15.
Article CAS PubMed Google Scholar
Dehghani M, Kargarfard M, Rabiee F, Nasr-Esfahani MH, Ghaedi K. A comparative study on the effects of acute and chronic downhill running vs uphill running exercise on the RNA levels of the skeletal muscles PGC1-α, FNDC5 and the adipose UCP1 in BALB/c mice. Gene. 2018;679:369–76.
Article CAS PubMed Google Scholar
Tanimura R, Kobayashi L, Shirai T, Takemasa T. Effects of exercise intensity on white adipose tissue browning and its regulatory signals in mice. Physiol Rep. 2022;10(5):e15205.
Article CAS PubMed PubMed Central Google Scholar
Rodrigues KCDC, Pereira RM, de Campos TDP, de Moura RF, da Silva ASR, Cintra DE, et al. The role of Physical Exercise to improve the Browning of White Adipose tissue via POMC neurons. Front Cell Neurosci. 2018;12:88.
Article PubMed PubMed Central Google Scholar
Zhu Y, Qi Z, Ding S. Exercise-Induced adipose tissue thermogenesis and Browning: how to explain the conflicting findings? Int J Mol Sci. 2022;23(21):13142.
Article CAS PubMed PubMed Central Google Scholar
Reisi J, Ghaedi K, Rajabi H, Marandi SM. Can Resistance Exercise Alter Irisin levels and expression profiles of FNDC5 and UCP1 in rats? Asian J Sports Med. 2016;7(4):e35205.
Article PubMed PubMed Central Google Scholar
Boström P, Wu J, Jedrychowski MP, Korde A, Ye L, Lo JC, et al. A PGC1-α-dependent myokine that drives brown-fat-like development of white fat and thermogenesis. Nature. 2012;481(7382):463–8.
Article PubMed PubMed Central Google Scholar
Brenmoehl J, Ohde D, Albrecht E, Walz C, Tuchscherer A, Hoeflich A. Browning of subcutaneous fat and higher surface temperature in response to phenotype selection for advanced endurance exercise performance in male DUhTP mice. J Comp Physiol B. 2017;187(2):361–73.
Article CAS PubMed Google Scholar
rving BA, Still CD, Argyropoulos G. Does IRISIN have a BRITE Future as a Therapeutic Agent in humans? Curr Obes Rep. 2014;3(2):235–41.
Article Google Scholar
Wang C, Zhang X, Liu M, Qin S, He C, Liu Y, et al. Irisin participates in the beneficial effects of exercise in preventing gestational diabetes mellitus in overweight and obese pregnant women and a mouse model. Front Nutr. 2023;9:1034443.
Article PubMed PubMed Central Google Scholar
Castillo-Quan JI. From white to brown fat through the PGC-1α-dependent myokine irisin: implications for diabetes and obesity. Dis Model Mech. 2012;5(3):293–5.
Article CAS PubMed PubMed Central Google Scholar
Brandao CFC, de Carvalho FG, Souza AO, Junqueira-Franco MVM, Batitucci G, Couto-Lima CA, et al. Physical training, UCP1 expression, mitochondrial density, and coupling in adipose tissue from women with obesity. Scand J Med Sci Sports. 2019;29(11):1699–706.
Article PubMed Google Scholar
Norheim F, Langleite TM, Hjorth M, Holen T, Kielland A, Stadheim HK, et al. The effects of acute and chronic exercise on PGC-1α, irisin and browning of subcutaneous adipose tissue in humans. FEBS J. 2014;281(3):739–49.
Article CAS PubMed Google Scholar
Martin AR, Chung S, Koehler K. Is Exercise a Match for Cold exposure? Common molecular Framework for Adipose tissue Browning. Int J Sports Med. 2020;41(7):427–42.
Article CAS PubMed Google Scholar
Ong FJ, Ahmed BA, Oreskovich SM, Blondin DP, Haq T, Konyer NB, et al. Recent advances in the detection of brown adipose tissue in adult humans: a review. Clin Sci (Lond). 2018;132(10):1039–54.
Article CAS PubMed Google Scholar
Vosselman MJ, Hoeks J, Brans B, Pallubinsky H, Nascimento EB, van der Lans AA, et al. Low brown adipose tissue activity in endurance-trained compared with lean sedentary men. Int J Obes (Lond). 2015;39(12):1696–702.
Article CAS PubMed Google Scholar
Ohyama K, Nogusa Y, Suzuki K, Shinoda K, Kajimura S, Bannai M. A combination of exercise and capsinoid supplementation additively suppresses diet-induced obesity by increasing energy expenditure in mice. Am J Physiol Endocrinol Metab. 2015;308(4):E315–23.
Article CAS PubMed Google Scholar
Gao Y, Wang Y, Zhou J, Hu Z, Shi Y. Effectiveness of electroacupuncture for simple obesity: a systematic review and Meta-analysis of Randomized controlled trials. Evid Based Complement Alternat Med. 2020;2020:2367610.
Article PubMed PubMed Central Google Scholar
Mi YQ. Clinical study on acupuncture for treatment of 80 cases of simple obesity. Zhongguo Zhen Jiu. 2005;25(2):95–7. Chinese. PMID: 16312889.
PubMed Google Scholar
Xinlu HE, Xuezhi L. Effect of ampk/sirt1 pathway and nrg4 content in adipose tissue regulated by electroacupuncture on browning of white fat in middle-aged and elderly obese rats. Acupunct Res. 2019;48(08):95–7.
Google Scholar
Zhu Ye T, Jun S, Yuwei, et al. Study on the mechanism of elec- troacupuncture to promote browning of white fat and improve obesity by regulating central glp-1. Acupunct Res. 2019;48:727–35.
Google Scholar
Yanji ZHANG, Wei H. Effect of electricity on pgc-1α/irisin/ucp1 signaling pathway in white adipose tissue of obese rats. Chin J Traditional Chin Med. 2022;14:3471–4.
Google Scholar
Lu SF, Tang YX, Zhang T, Fu SP, Hong H, Cheng Y, et al. Electroacupuncture reduces Body Weight by regulating Fat Browning-related proteins of adipose tissue in HFD-Induced obese mice. Front Psychiatry. 2019;10:353.
Article PubMed PubMed Central Google Scholar
Shen W, Wang Y, Lu SF, Hong H, Fu S, He S, et al. Acupuncture promotes white adipose tissue browning by inducing UCP1 expression on DIO mice. BMC Complement Altern Med. 2014;14:501.
Article PubMed PubMed Central Google Scholar
Tang Q, Lu M, Xu B, Wang Y, Lu S, Yu Z, Jing X, Yuan J. Electroacupuncture regulates Inguinal White Adipose tissue Browning by promoting Sirtuin-1-Dependent PPARγ deacetylation and mitochondrial Biogenesis. Front Endocrinol (Lausanne). 2021;11:607113.
Article PubMed Google Scholar
Lu Y, Li G. Auricular acupuncture induces FNDC5/irisin and attenuates obese inflammation in mice. Acupunct Med. 2020;38(4):264–71.
Article PubMed Google Scholar
Jin Y. Study on the mechanism of embedding at back-shu point on obesity in ovx rats based on fat energy metabolism. Liaoning University of Chinese Medicine; 2020.
Shimada T, Kudo T, Akase T, Aburada M. Preventive effects of Bofutsushosan on obesity and various metabolic disorders. Biol Pharm Bull. 2008;31(7):1362–7.
Article CAS PubMed Google Scholar
Chen YY, Yan Y, Zhao Z, Shi MJ, Zhang YB. Bofutsushosan ameliorates obesity in mice through modulating PGC-1α expression in brown adipose tissues and inhibiting inflammation in white adipose tissues. Chin J Nat Med. 2016;14(6):449–56.
CAS PubMed Google Scholar
Akagiri S, Naito Y, Ichikawa H, Mizushima K, Takagi T, Handa O, et al. Bofutsushosan, an oriental Herbal Medicine, attenuates the Weight Gain of White Adipose tissue and the increased size of Adipocytes Associated with the increase in their expression of uncoupling protein 1 in High-Fat Diet-Fed Male KK/Ta mice. J Clin Biochem Nutr. 2008;42(2):158–66.
Article PubMed PubMed Central Google Scholar
Zu YX, Lu HY, Liu WW, Jiang XW, Huang Y, Li X, et al. Jiang Gui Fang activated interscapular brown adipose tissue and induced epididymal white adipose tissue browning through the PPARγ/SIRT1-PGC1α pathway. J Ethnopharmacol. 2020;248:112271.
Article CAS PubMed Google Scholar
Liu X, Gao YP, Shen ZX, Qu YY, Liu WW, Yao D, et al. Study on the experimental verification and regulatory mechanism of Rougui-Ganjiang herb-pair for the actions of thermogenesis in brown adipose tissue based on network pharmacology. J Ethnopharmacol. 2021;279:114378.
Article CAS PubMed Google Scholar
Yao D, Xing B, Li X, Xu ZH, Liu Q, Liu X, et al. Integrated UHPLC-QE/MS, transcriptomics and network pharmacology reveal the mechanisms via which Liang-Yan-Yi-Zhen-San promotes the browning of white adipose tissue. Biomed Chromatogr. 2023;37(12):e5734.
Article CAS PubMed Google Scholar
Hao M, Guan Z, Gao Y, Xing J, Zhou X, Wang C, et al. Huang-Qi San ameliorates hyperlipidemia with obesity rats via activating brown adipocytes and converting white adipocytes into brown-like adipocytes. Phytomedicine. 2020;78:153292.
Article CAS PubMed Google Scholar
Xu BW, Fang Z, Xuxin, et al. Effect of huangqi powder on body fat coefficient and mrna expression of mcp-1, ucp-1, prdm16 and cidea in adipose tissue of t2dm rats. J Chin Med. 2018;10(4):2345–8.
Google Scholar
Song DZ, Huimin, Zeng Mingxing. Effect of wenshen jianpi huatan formula on gene expression of pparγ/pgc-1α/ucp1 pathway in obese rats. Hubei J Traditional Chin Med. 2023;45(1):3–6.
Google Scholar
Xu J, Zhang LW, Feng H, Tang Y, Fu SQ, Liu XM, et al. The Chinese herbal medicine Dai-Zong-Fang promotes browning of white adipocytes in vivo and in vitro by activating PKA pathway to ameliorate obesity. Front Pharmacol. 2023;14:1176443.
Article CAS PubMed PubMed Central Google Scholar
Kang OH, Shon MY, Kong R, Seo YS, Zhou T, Kim DY, et al. Anti-diabetic effect of black ginseng extract by augmentation of AMPK protein activity and upregulation of GLUT2 and GLUT4 expression in db/db mice. BMC Complement Altern Med. 2017;17(1):341.
Article PubMed PubMed Central Google Scholar
Park SJ, Park M, Sharma A, Kim K, Lee HJ. Black ginseng and Ginsenoside Rb1 Promote Browning by inducing UCP1 expression in 3T3-L1 and primary White adipocytes. Nutrients. 2019;11(11):2747.
Article CAS PubMed PubMed Central Google Scholar
Sun BS, Gu LJ, Fang ZM, Wang CY, Wang Z, Lee MR, et al. Simultaneous quantification of 19 ginsenosides in black ginseng developed from Panax ginseng by HPLC-ELSD. J Pharm Biomed Anal. 2009;50(1):15–22.
Article CAS PubMed Google Scholar
Lee K, Seo YJ, Song JH, Chei S, Lee BY. Ginsenoside Rg1 promotes browning by inducing UCP1 expression and mitochondrial activity in 3T3-L1 and subcutaneous white adipocytes. J Ginseng Res. 2019;43(4):589–99.
Article PubMed Google Scholar
Chen G, Li H, Zhao Y, Zhu H, Cai E, Gao Y, et al. Saponins from stems and leaves of Panax ginseng prevent obesity via regulating thermogenesis, lipogenesis and lipolysis in high-fat diet-induced obese C57BL/6 mice. Food Chem Toxicol. 2017;106(Pt A):393–403.
Article CAS PubMed Google Scholar
Kong W, Wei J, Abidi P, Lin M, Inaba S, Li C, et al. Berberine is a novel cholesterol-lowering drug working through a unique mechanism distinct from statins. Nat Med. 2004;10(12):1344–51.
Article CAS PubMed Google Scholar
Zhang Z, Zhang H, Li B, Meng X, Wang J, Zhang Y, et al. Berberine activates thermogenesis in white and brown adipose tissue. Nat Commun. 2014;5:5493.
Article CAS PubMed Google Scholar
Wang Q, Xu X, Jiang X, Yin F. Berberine regulates UCP1 expression by reshaping the conformation of quadruplex formed by the element of the UCP1 gene promoter. Acta Biochim Biophys Sin (Shanghai). 2022;54(11):1757–60.
Article PubMed Google Scholar
Xu Y, Yu T, Ma G, Zheng L, Jiang X, Yang F, et al. Berberine modulates deacetylation of PPARγ to promote adipose tissue remodeling and thermogenesis via AMPK/SIRT1 pathway. Int J Biol Sci. 2021;17(12):3173–87.
Article CAS PubMed PubMed Central Google Scholar
Hao M, Li Y, Liu L, Yuan X, Gao Y, Guan Z, et al. The design and synthesis of a novel compound of berberine and baicalein that inhibits the efficacy of lipid accumulation in 3T3-L1 adipocytes. Bioorg Med Chem. 2017;25(20):5506–12.
Article CAS PubMed Google Scholar
Kubra IR, Rao LJ. An impression on current developments in the technology, chemistry, and biological activities of ginger (Zingiber officinale Roscoe). Crit Rev Food Sci Nutr. 2012;52(8):651–88.
Article CAS PubMed Google Scholar
Ballester P, Cerdá B, Arcusa R, Marhuenda J, Yamedjeu K, Zafrilla P. Effect of Ginger on Inflammatory diseases. Molecules. 2022;27(21):7223.
Article CAS PubMed PubMed Central Google Scholar
Ebrahimzadeh Attari V, Asghari Jafarabadi M, Zemestani M, Ostadrahimi A. Effect of Zingiber officinale supplementation on obesity management with respect to the uncoupling protein 1-3826A > G and β3-adrenergic receptor Trp64Arg polymorphism. Phytother Res. 2015;29(7):1032–9.
Article CAS PubMed Google Scholar
Gong G, Han G, He H, Dong TTX, Tsim KWK, Zheng Y. An ancient Chinese herbal decoction containing Angelicae sinensis Radix, Astragali Radix, Jujuba Fructus, and Zingiberis Rhizoma Recens stimulates the Browning Conversion of White Adipocyte in cultured 3T3-L1 cells. Evid Based Complement Alternat Med. 2019;2019:3648685.
Article PubMed PubMed Central Google Scholar
Li X, Yao Y, Yu C, Wei T, Xi Q, Li J, et al. Modulation of PPARα-thermogenesis gut microbiota interactions in obese mice administrated with zingerone. J Sci Food Agric. 2023;103(6):3065–76.
Article CAS PubMed Google Scholar
Wang J, Zhang L, Dong L, Hu X, Feng F, Chen F. 6-Gingerol, a functional polyphenol of Ginger, Promotes Browning through an AMPK-Dependent pathway in 3T3-L1 adipocytes. J Agric Food Chem. 2019;67(51):14056–65.
Article CAS PubMed Google Scholar
Lee EJ, Oh H, Kang BG, Kang MK, Kim DY, Kim YH, et al. Lipid-lowering effects of medium-chain triglyceride-enriched Coconut Oil in combination with licorice extracts in experimental hyperlipidemic mice. J Agric Food Chem. 2018;66(40):10447–57.
Article CAS PubMed Google Scholar
Lee HE, Yang G, Han SH, Lee JH, An TJ, Jang JK, et al. Anti-obesity potential of Glycyrrhiza uralensis and licochalcone A through induction of adipocyte browning. Biochem Biophys Res Commun. 2018;503(3):2117–23.
Article CAS PubMed Google Scholar
Li X, Lu HY, Jiang XW, Yang Y, Xing B, Yao D, et al. Cinnamomum cassia extract promotes thermogenesis during exposure to cold via activation of brown adipose tissue. J Ethnopharmacol. 2021;266:113413.
Article CAS PubMed Google Scholar
Zuo J, Zhao D, Yu N, Fang X, Mu Q, Ma Y, et al. Cinnamaldehyde ameliorates Diet-Induced obesity in mice by Inducing Browning of White Adipose tissue. Cell Physiol Biochem. 2017;42(4):1514–25.
Article CAS PubMed Google Scholar
Neto JGO, Boechat SK, Romão JS, Kuhnert LRB, Pazos-Moura CC, Oliveira KJ. Cinnamaldehyde treatment during adolescence improves white and brown adipose tissue metabolism in a male rat model of early obesity. Food Funct. 2022;13(6):3405–18.
Article CAS PubMed Google Scholar
Kang NH, Mukherjee S, Yun JW. Trans-Cinnamic Acid stimulates White Fat Browning and activates brown adipocytes. Nutrients. 2019;11(3):577.
Article CAS PubMed PubMed Central Google Scholar
Khare P, Mangal P, Baboota RK, Jagtap S, Kumar V, Singh DP, et al. Involvement of Glucagon in Preventive Effect of Menthol Against High Fat Diet Induced Obesity in mice. Front Pharmacol. 2018;9:1244.
Article CAS PubMed PubMed Central Google Scholar
Sanders OD, Rajagopal JA, Rajagopal L. Menthol to induce non-shivering thermogenesis via TRPM8/PKA Signaling for Treatment of Obesity. J Obes Metab Syndr. 2021;30(1):4–11.
Article PubMed Google Scholar
Khare P, Chauhan A, Kumar V, Kaur J, Mahajan N, Kumar V, et al. Bioavailable menthol (transient receptor potential Melastatin-8 agonist) induces Energy Expending phenotype in differentiating adipocytes. Cells. 2019;8(5):383.
Article CAS PubMed PubMed Central Google Scholar
Liu M, Zhang JF, Zhu WL, Liu H, Jia X. Loureirin B protects against obesity via activation of adipose tissue ω3 PUFA-GPR120-UCP1 axis in mice. Biochem Biophys Res Commun. 2022;632:139–49.
Article CAS PubMed Google Scholar
Bartoňková I, Dvořák Z. Essential oils of culinary herbs and spices display agonist and antagonist activities at human aryl hydrocarbon receptor AhR. Food Chem Toxicol. 2018;111:374–84.
Article PubMed Google Scholar
Kang NH, Mukherjee S, Min T, Kang SC, Yun JW. Trans-Anethole ameliorates obesity via induction of browning in white adipocytes and activation of brown adipocytes. Biochimie. 2018;151:1–13.
Article CAS PubMed Google Scholar
Song Z, Revelo X, Shao W, Tian L, Zeng K, Lei H, et al. Dietary curcumin intervention targets mouse White Adipose tissue inflammation and brown adipose tissue UCP1 expression. Obes (Silver Spring). 2018;26(3):547–58.
Article CAS Google Scholar
Wang S, Wang X, Ye Z, Xu C, Zhang M, Ruan B, et al. Curcumin promotes browning of white adipose tissue in a norepinephrine-dependent way. Biochem Biophys Res Commun. 2015;466(2):247–53.
Article CAS PubMed Google Scholar
Reyad-Ul-Ferdous M, Song Y. Baicalein modulates mitochondrial function by upregulating mitochondrial uncoupling protein-1 (UCP1) expression in brown adipocytes, cytotoxicity, and computational studies. Int J Biol. 2022;222(Pt B):1963–73.
CAS Google Scholar
Kuo KL, Weng MS, Chiang CT, Tsai YJ, Lin-Shiau SY, Lin JK. Comparative studies on the hypolipidemic and growth suppressive effects of oolong, black, pu-erh, and green tea leaves in rats. J Agric Food Chem. 2005;53(2):480–9.
Article CAS PubMed Google Scholar
Yamashita Y, Wang L, Wang L, Tanaka Y, Zhang T, Ashida H. Oolong, black and Pu-Erh tea suppresses adiposity in mice via activation of AMP-activated protein kinase. Food Funct. 2014;5(10):2420–9.
Article CAS PubMed Google Scholar
Bolin AP, Sousa-Filho CPB, Dos Santos GTN, Ferreira LT, de Andrade PBM, Figueira ACM, et al. Adipogenic commitment induced by green tea polyphenols remodel adipocytes to a thermogenic phenotype. J Nutr Biochem. 2020;83:108429.
Article CAS PubMed Google Scholar
Neyrinck AM, Bindels LB, Geurts L, Van Hul M, Cani PD, Delzenne NM. A polyphenolic extract from green tea leaves activates fat browning in high-fat-diet-induced obese mice. J Nutr Biochem. 2017;49:15–21.
Article CAS PubMed Google Scholar
Chen LH, Chien YW, Liang CT, Chan CH, Fan MH, Huang HY. Green tea extract induces genes related to browning of white adipose tissue and limits weight-gain in high energy diet-fed rat. Food Nutr Res. 2017;61(1):1347480.
Article PubMed PubMed Central Google Scholar
Im H, Lee J, Kim K, Son Y, Lee YH. Anti-obesity effects of heat-transformed green tea extract through the activation of adipose tissue thermogenesis. Nutr Metab (Lond). 2022;19(1):14.
Article CAS PubMed Google Scholar
Tung YC, Liang ZR, Yang MJ, Ho CT, Pan MH. Oolong tea extract alleviates weight gain in high-fat diet-induced obese rats by regulating lipid metabolism and modulating gut microbiota. Food Funct. 2022;13(5):2846–56.
Article CAS PubMed Google Scholar
Xu N, Chu J, Dong R, Lu F, Zhang X, Wang M, et al. Yellow tea stimulates thermogenesis in mice through Heterogeneous Browning of adipose tissues. Mol Nutr Food Res. 2021;65(2):e2000864.
Article PubMed Google Scholar
Wang Y, Li T, Yang C, Wu Y, Liu Y, Yang X. Eurotium Cristatum from Fu Brick Tea promotes adipose thermogenesis by boosting Colonic Akkermansia muciniphila in High-Fat-Fed obese mice. Foods. 2023;12(20):3716.
Article CAS PubMed PubMed Central Google Scholar
Wang Y, Zhao A, Du H, Liu Y, Qi B, Yang X. Theabrownin from Fu Brick Tea exhibits the thermogenic function of adipocytes in High-Fat-Diet-Induced obesity. J Agric Food Chem. 2021;69(40):11900–11.
Article CAS PubMed Google Scholar
Yan J, Bak J, Go Y, Park J, Park M, Lee HJ, et al. Scytosiphon lomentaria Extract ameliorates obesity and modulates gut microbiota in High-Fat-Diet-Fed mice. Nutrients. 2023;15(4):815.
Article CAS PubMed PubMed Central Google Scholar
Kim D, Yan J, Bak J, Park J, Lee H, Kim H. Sargassum Thunbergii Extract attenuates high-Fat Diet-Induced obesity in mice by modulating AMPK activation and the gut microbiota. Foods. 2022;11(16):2529.
Article CAS PubMed PubMed Central Google Scholar
Kang MC, Lee HG, Kim HS, Song KM, Chun YG, Lee MH, et al. Anti-obesity effects of Sargassum thunbergii via downregulation of Adipogenesis Gene and upregulation of thermogenic genes in High-Fat Diet-Induced obese mice. Nutrients. 2020;12(11):3325.
Article PubMed PubMed Central Google Scholar
Lu YA, Lee HG, Li X, Hyun JM, Kim HS, Kim TH, et al. Anti-obesity effects of red seaweed, Plocamium telfairiae, in C57BL/6 mice fed a high-fat diet. Food Funct. 2020;11(3):2299–308.
Article CAS PubMed Google Scholar
Okla M, Kim J, Koehler K, Chung S. Dietary factors promoting Brown and Beige Fat development and thermogenesis. Adv Nutr. 2017;8(3):473–83.
Article CAS PubMed PubMed Central Google Scholar
Darby JRT, Mohd Dollah MHB, Regnault TRH, Williams MT, Morrison JL. Systematic review: impact of resveratrol exposure during pregnancy on maternal and fetal outcomes in animal models of human pregnancy complications-are we ready for the clinic? Pharmacol Res. 2019;144:264–78.
Article CAS PubMed Google Scholar
Xia N, Daiber A, Förstermann U, Li H. Antioxidant effects of resveratrol in the cardiovascular system. Br J Pharmacol. 2017;174(12):1633–46.
Article CAS PubMed Google Scholar
Cho S, Namkoong K, Shin M, Park J, Yang E, Ihm J, et al. Cardiovascular Protective effects and clinical applications of Resveratrol. J Med Food. 2017;20(4):323–34.
Article CAS PubMed Google Scholar
Andrade JM, Frade AC, Guimarães JB, Freitas KM, Lopes MT, Guimarães AL, et al. Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet. Eur J Nutr. 2014;53(7):1503–10.
Article CAS PubMed Google Scholar
Andrade JMO, Barcala-Jorge AS, Batista-Jorge GC, Paraíso AF, Freitas KM, Lelis DF, et al. Effect of resveratrol on expression of genes involved thermogenesis in mice and humans. Biomed Pharmacother. 2019;112:108634.
Article CAS PubMed Google Scholar
Zu Y, Overby H, Ren G, Fan Z, Zhao L, Wang S. Resveratrol liposomes and lipid nanocarriers: comparison of characteristics and inducing browning of white adipocytes. Colloids Surf B Biointerfaces. 2018;164:414–23.
Article CAS PubMed Google Scholar
Alberdi G, Rodríguez VM, Miranda J, Macarulla MT, Churruca I, Portillo MP. Thermogenesis is involved in the body-fat lowering effects of resveratrol in rats. Food Chem. 2013;141(2):1530–5.
Article CAS PubMed Google Scholar
Hui S, Liu Y, Huang L, Zheng L, Zhou M, Lang H, et al. Resveratrol enhances brown adipose tissue activity and white adipose tissue browning in part by regulating bile acid metabolism via gut microbiota remodeling. Int J Obes (Lond). 2020;44(8):1678–90.
Article CAS PubMed Google Scholar
Ravaud C, Paré M, Yao X, Azoulay S, Mazure NM, Dani C, et al. Resveratrol and HIV-protease inhibitors control UCP1 expression through opposite effects on p38 MAPK phosphorylation in human adipocytes. J Cell Physiol. 2020;235(2):1184–96.
Article CAS PubMed Google Scholar
Shaito A, Posadino AM, Younes N, Hasan H, Halabi S, Alhababi D, et al. Potential adverse effects of Resveratrol: A literature review. Int J Mol Sci. 2020;21(6):2084.
Article CAS PubMed PubMed Central Google Scholar
Farhan M, Rizvi A. The Pharmacological properties of red grape Polyphenol Resveratrol: clinical trials and obstacles in Drug Development. Nutrients. 2023;15(20):4486.
Article CAS PubMed PubMed Central Google Scholar
Salehi B, Mishra AP, Nigam M, Sener B, Kilic M, Sharifi-Rad M, et al. Resveratrol: a double-edged Sword in Health benefits. Biomedicines. 2018;6(3):91.
Article CAS PubMed PubMed Central Google Scholar
Lee YM, Yoon Y, Yoon H, Park HM, Song S, Yeum KJ. Dietary anthocyanins against obesity and inflammation. Nutrients. 2017;9(10):1089.
Article PubMed PubMed Central Google Scholar
You Y, Yuan X, Liu X, Liang C, Meng M, Huang Y et al. Cyanidin-3-glucoside increases whole body energy metabolism by upregulating brown adipose tissue mitochondrial function. Mol Nutr Food Res. 2017;61(11).
Han S, Yang Y, Lu Y, Guo J, Han X, Gao Y, et al. Cyanidin-3-O-glucoside regulates the expression of Ucp1 in Brown Adipose tissue by activating Prdm16 gene. Antioxid (Basel). 2021;10(12):1986.
Article CAS Google Scholar
Molonia MS, Salamone FL, Muscarà C, Costa G, Vento G, Saija A, et al. Regulation of mitotic clonal expansion and thermogenic pathway are involved in the antiadipogenic effects of cyanidin-3-O-glucoside. Front Pharmacol. 2023;14:1225586.
Article CAS PubMed PubMed Central Google Scholar
Maeda H, Hosokawa M, Sashima T, Funayama K, Miyashita K. Fucoxanthin from edible seaweed, Undaria Pinnatifida, shows antiobesity effect through UCP1 expression in white adipose tissues. Biochem Biophys Res Commun. 2005;332(2):392–7.
Article CAS PubMed Google Scholar
Jeon SM, Kim HJ, Woo MN, Lee MK, Shin YC, Park YB, et al. Fucoxanthin-rich seaweed extract suppresses body weight gain and improves lipid metabolism in high-fat-fed C57BL/6J mice. Biotechnol J. 2010;5(9):961–9.
Article CAS PubMed Google Scholar
Miyashita K, Nishikawa S, Beppu F, Tsukui T, Abe M, Hosokawa M. The allenic carotenoid fucoxanthin, a novel marine nutraceutical from brown seaweeds. J Sci Food Agric. 2011;91(7):1166–74.
Article CAS PubMed Google Scholar
Grasa-López A, Miliar-García Á, Quevedo-Corona L, Paniagua-Castro N, Escalona-Cardoso G, Reyes-Maldonado E, et al. Undaria pinnatifida and Fucoxanthin Ameliorate Lipogenesis and markers of both inflammation and Cardiovascular Dysfunction in an animal model of Diet-Induced obesity. Mar Drugs. 2016;14(8):148.
Article PubMed PubMed Central Google Scholar
Peng J, Yuan JP, Wu CF, Wang JH. Fucoxanthin, a marine carotenoid present in brown seaweeds and diatoms: metabolism and bioactivities relevant to human health. Mar Drugs. 2011;9(10):1806–28.
Article CAS PubMed PubMed Central Google Scholar
Koo SY, Hwang JH, Yang SH, Um JI, Hong KW, Kang K, et al. Anti-obesity effect of standardized extract of Microalga Phaeodactylum tricornutum Containing Fucoxanthin. Mar Drugs. 2019;17(5):311.
Article CAS PubMed PubMed Central Google Scholar
Woo MN, Jeon SM, Shin YC, Lee MK, Kang MA, Choi MS. Anti-obese property of fucoxanthin is partly mediated by altering lipid-regulating enzymes and uncoupling proteins of visceral adipose tissue in mice. Mol Nutr Food Res. 2009;53(12):1603–11.
Article CAS PubMed Google Scholar
Gille A, Stojnic B, Derwenskus F, Trautmann A, Schmid-Staiger U, Posten C, et al. A lipophilic Fucoxanthin-Rich Phaeodactylum tricornutum Extract ameliorates effects of Diet-Induced obesity in C57BL/6J mice. Nutrients. 2019;11(4):796.
Article CAS PubMed PubMed Central Google Scholar
Mikami N, Hosokawa M, Miyashita K, Sohma H, Ito YM, Kokai Y. Reduction of HbA1c levels by fucoxanthin-enriched akamoku oil possibly involves the thrifty allele of uncoupling protein 1 (UCP1): a randomised controlled trial in normal-weight and obese Japanese adults. J Nutr Sci. 2017;6:e5.
Article PubMed PubMed Central Google Scholar
Asai A, Yonekura L, Nagao A. Low bioavailability of dietary epoxyxanthophylls in humans. Br J Nutr. 2008;100(2):273–7.
Article CAS PubMed Google Scholar
Nomura S, Ichinose T, Jinde M, Kawashima Y, Tachiyashiki K, Imaizumi K. Tea catechins enhance the mRNA expression of uncoupling protein 1 in rat brown adipose tissue. J Nutr Biochem. 2008;19(12):840–7.
Article CAS PubMed Google Scholar
Mi Y, Liu X, Tian H, Liu H, Li J, Qi G, Liu X. EGCG stimulates the recruitment of brite adipocytes, suppresses adipogenesis and counteracts TNF-α-triggered insulin resistance in adipocytes. Food Funct. 2018;9(6):3374–86.
Article CAS PubMed Google Scholar
Chatree S, Sitticharoon C, Maikaew P, Pongwattanapakin K, Keadkraichaiwat I, Churintaraphan M, et al. Epigallocatechin gallate decreases plasma triglyceride, blood pressure, and serum kisspeptin in obese human subjects. Exp Biol Med (Maywood). 2021;246(2):163–76.
Article CAS PubMed Google Scholar
Oruganti L, Reddy Sankaran K, Dinnupati HG, Kotakadi VS, Meriga B. Anti-adipogenic and lipid-lowering activity of piperine and epigallocatechin gallate in 3T3-L1 adipocytes. Arch Physiol Biochem. 2023;129(5):1152–9.
Article CAS PubMed Google Scholar
Klaus S, Pültz S, Thöne-Reineke C, Wolfram S. Epigallocatechin gallate attenuates diet-induced obesity in mice by decreasing energy absorption and increasing fat oxidation. Int J Obes (Lond). 2005;29(6):615–23.
Article CAS PubMed Google Scholar
Kim HS, Moon JH, Kim YM, Huh JY. Epigallocatechin exerts Anti-obesity Effect in Brown Adipose tissue. Chem Biodivers. 2019;16(10):e1900347.
Article CAS PubMed Google Scholar
Baskaran P, Krishnan V, Ren J, Thyagarajan B. Capsaicin induces browning of white adipose tissue and counters obesity by activating TRPV1 channel-dependent mechanisms. Br J Pharmacol. 2016;173(15):2369–89.
Article CAS PubMed PubMed Central Google Scholar
Panchal SK, Bliss E, Brown L. Capsaicin in Metabolic Syndrome. Nutrients. 2018;10(5):630.
Article PubMed PubMed Central Google Scholar
Montanari T, Boschi F, Colitti M. Comparison of the effects of Browning-Inducing Capsaicin on two murine adipocyte models. Front Physiol. 2019;10:1380.
Article PubMed PubMed Central Google Scholar
Takeda Y, Dai P. Capsaicin directly promotes adipocyte browning in the chemical compound-induced brown adipocytes converted from human dermal fibroblasts. Sci Rep. 2022;12(1):6612.
Article CAS PubMed PubMed Central Google Scholar
Chen S, Liu X, Peng C, Tan C, Sun H, Liu H, et al. The phytochemical hyperforin triggers thermogenesis in adipose tissue via a Dlat-AMPK signaling axis to curb obesity. Cell Metab. 2021;33(3):565–e5807.
Article CAS PubMed Google Scholar
Chou YC, Ho CT, Pan MH. Immature Citrus reticulata Extract promotes Browning of Beige adipocytes in High-Fat Diet-Induced C57BL/6 mice. J Agric Food Chem. 2018;66(37):9697–703.
Article CAS PubMed Google Scholar
Kihara-Negishi F, Ohkura N, Takahashi Y, Fujita T, Nakamura Y, Maruyama K, et al. Nobiletin and 3’-Demethyl Nobiletin Activate Brown adipocytes upon β-Adrenergic stimulation. Biol Pharm Bull. 2022;45(4):528–33.
Article CAS PubMed Google Scholar
Liu Z, Qiao Q, Sun Y, Chen Y, Ren B, Liu X. Sesamol ameliorates diet-induced obesity in C57BL/6J mice and suppresses adipogenesis in 3T3-L1 cells via regulating mitochondria-lipid metabolism. Mol Nutr Food Res. 2017;61(8).
Lin C, Chen J, Hu M, Zheng W, Song Z, Qin H. Sesamol promotes browning of white adipocytes to ameliorate obesity by inducing mitochondrial biogenesis and inhibition mitophagy via β3-AR/PKA signaling pathway. Food Nutr Res. 2021;65.
Lee DH, Chang SH, Yang DK, Song NJ, Yun UJ, Park KW. Sesamol increases Ucp1 expression in White Adipose tissues and stimulates Energy Expenditure in High-Fat Diet-Fed obese mice. Nutrients. 2020;12(5):1459.
Article PubMed PubMed Central Google Scholar
Pei Y, Otieno D, Gu I, Lee SO, Parks JS, Schimmel K, et al. Effect of quercetin on nonshivering thermogenesis of brown adipose tissue in high-fat diet-induced obese mice. J Nutr Biochem. 2021;88:108532.
Article CAS PubMed Google Scholar
Liu X, Feng X, Deng C, Liu L, Zeng Y, Hu CH. Brown adipose tissue activity is modulated in olanzapine-treated young rats by simvastatin. BMC Pharmacol Toxicol. 2020;21(1):48.
Article CAS PubMed PubMed Central Google Scholar
Mäuser W, Perwitz N, Meier B, Fasshauer M, Klein J. Direct adipotropic actions of atorvastatin: differentiation state-dependent induction of apoptosis, modulation of endocrine function, and inhibition of glucose uptake. Eur J Pharmacol. 2007;564(1–3):37–46.
Article PubMed Google Scholar
Balaz M, Becker AS, Balazova L, Straub L, Müller J, Gashi G, et al. Inhibition of Mevalonate Pathway prevents Adipocyte Browning in mice and men by affecting protein prenylation. Cell Metab. 2019;29(4):901–e9168.
Article CAS PubMed Google Scholar
Arch JR, Ainsworth AT, Cawthorne MA, Piercy V, Sennitt MV, Thody VE, et al. Atypical beta-adrenoceptor on brown adipocytes as target for anti-obesity drugs. Nature. 1984;309(5964):163–5.
Article CAS PubMed Google Scholar
Smith DL Jr, Yarar-Fisher C. Contributors to metabolic Disease Risk following spinal cord Injury. Curr Phys Med Rehabil Rep. 2016;4(3):190–9.
Article PubMed PubMed Central Google Scholar
Merlin J, Sato M, Nowell C, Pakzad M, Fahey R, Gao J, et al. The PPARγ agonist rosiglitazone promotes the induction of brite adipocytes, increasing β-adrenoceptor-mediated mitochondrial function and glucose uptake. Cell Signal. 2018;42:54–66.
Article CAS PubMed Google Scholar
Merlin J, Sato M, Chia LY, Fahey R, Pakzad M, Nowell CJ, et al. Rosiglitazone and a β3-Adrenoceptor agonist are both required for Functional Browning of White adipocytes in Culture. Front Endocrinol (Lausanne). 2018;9:249.
Article PubMed Google Scholar
Himms-Hagen J, Cui J, Danforth E Jr, Taatjes DJ, Lang SS, Waters BL, et al. Effect of CL-316,243, a thermogenic beta 3-agonist, on energy balance and brown and white adipose tissues in rats. Am J Physiol. 1994;266(4 Pt 2):R1371–82.
CAS PubMed Google Scholar
Ghorbani M, Teimourian S, Farzad R, Asl NN. Apparent histological changes of adipocytes after treatment with CL 316,243, a β3-adrenergic receptor agonist. Drug Des Devel Ther. 2015;9:669–76.
Article CAS PubMed PubMed Central Google Scholar
Blondin DP, Nielsen S, Kuipers EN, Severinsen MC, Jensen VH, Miard S, et al. Human brown adipocyte thermogenesis is driven by β2-AR stimulation. Cell Metab. 2020;32(2):287–e3007.
Article CAS PubMed Google Scholar
O’Mara AE, Johnson JW, Linderman JD, Brychta RJ, McGehee S, Fletcher LA, et al. Chronic mirabegron treatment increases human brown fat, HDL cholesterol, and insulin sensitivity. J Clin Invest. 2020;130(5):2209–19.
Article PubMed PubMed Central Google Scholar
Finlin BS, Memetimin H, Zhu B, Confides AL, Vekaria HJ, El Khouli RH, et al. The β3-adrenergic receptor agonist mirabegron improves glucose homeostasis in obese humans. J Clin Invest. 2020;130(5):2319–31.
Article CAS PubMed PubMed Central Google Scholar
Dehvari N, Sato M, Bokhari MH, Kalinovich A, Ham S, Gao J, et al. The metabolic effects of mirabegron are mediated primarily by β3-adrenoceptors. Pharmacol Res Perspect. 2020;8(5):e00643.
Article CAS PubMed PubMed Central Google Scholar
Cero C, Lea HJ, Zhu KY, Shamsi F, Tseng YH, Cypess AM. β3-Adrenergic receptors regulate human brown/beige adipocyte lipolysis and thermogenesis. JCI Insight. 2021;6(11):e139160.
Article PubMed PubMed Central Google Scholar
Gross B, Pawlak M, Lefebvre P, Staels B. PPARs in obesity-induced T2DM, dyslipidaemia and NAFLD. Nat Rev Endocrinol. 2017;13(1):36–49.
Article CAS PubMed Google Scholar
Mahmoudi A, Ghatreh Samani K, Amini SA, Heidarian E. Effects of Pioglitazone on the lipid Profile, serum antioxidant capacity, and UCP1 gene expression in Mouse Brown Adipose tissue. Rep Biochem Mol Biol. 2019;8(1):15–20.
CAS PubMed PubMed Central Google Scholar
Tutunchi H, Ostadrahimi A, Saghafi-Asl M, Hosseinzadeh-Attar MJ, Shakeri A, Asghari-Jafarabadi M, et al. Oleoylethanolamide supplementation in obese patients newly diagnosed with non-alcoholic fatty liver disease: effects on metabolic parameters, anthropometric indices, and expression of PPAR-α, UCP1, and UCP2 genes. Pharmacol Res. 2020;156:104770.
Article CAS PubMed Google Scholar
Bortolini M, Wright MB, Bopst M, Balas B. Examining the safety of PPAR agonists - current trends and future prospects. Expert Opin Drug Saf. 2013;12(1):65–79.
Article CAS PubMed Google Scholar
Sakellariou P, Valente A, Carrillo AE, Metsios GS, Nadolnik L, Jamurtas AZ, et al. Chronic l-menthol-induced browning of white adipose tissue hypothesis: a putative therapeutic regime for combating obesity and improving metabolic health. Med Hypotheses. 2016;93:21–6.
Article CAS PubMed Google Scholar
Rossato M, Granzotto M, Macchi V, Porzionato A, Petrelli L, Calcagno A, et al. Human white adipocytes express the cold receptor TRPM8 which activation induces UCP1 expression, mitochondrial activation and heat production. Mol Cell Endocrinol. 2014;383(1–2):137–46.
Article CAS PubMed Google Scholar
Jiang C, Zhai M, Yan D, Li D, Li C, Zhang Y, et al. Dietary menthol-induced TRPM8 activation enhances WAT browning and ameliorates diet-induced obesity. Oncotarget. 2017;8(43):75114–26.
Article PubMed PubMed Central Google Scholar
Bautista DM, Siemens J, Glazer JM, Tsuruda PR, Basbaum AI, Stucky CL, Jordt SE, Julius D. The menthol receptor TRPM8 is the principal detector of environmental cold. Nature. 2007;448(7150):204–8.
Article CAS PubMed Google Scholar
Ma S, Yu H, Zhao Z, Luo Z, Chen J, Ni Y, et al. Activation of the cold-sensing TRPM8 channel triggers UCP1-dependent thermogenesis and prevents obesity. J Mol Cell Biol. 2012;4(2):88–96.
Article CAS PubMed Google Scholar
Zhuang S, Chai J, Liu L, Yin H, Yu Y. Effect of celecoxib in treatment of burn-induced hypermetabolism. Biosci Rep. 2020;40(4):BSR20191607.
Article PubMed PubMed Central Google Scholar
Choi SE, Jang HJ, Kang Y, Jung JG, Han SJ, Kim HJ, et al. Atherosclerosis induced by a high-fat diet is alleviated by lithium chloride via reduction of VCAM expression in ApoE-deficient mice. Vascul Pharmacol. 2010;53(5–6):264–72.
Article CAS PubMed Google Scholar
Fajardo VA, Fajardo VA, LeBlanc PJ, MacPherson REK. Examining the relationship between Trace Lithium in drinking Water and the Rising Rates of Age-Adjusted Alzheimer’s Disease Mortality in Texas. J Alzheimers Dis. 2018;61(1):425–34.
Article CAS PubMed Google Scholar
Geromella MS, Ryan CR, Braun JL, Finch MS, Maddalena LA, Bagshaw O, et al. Low-dose lithium supplementation promotes adipose tissue browning and sarco(endo)plasmic reticulum Ca2 + ATPase uncoupling in muscle. J Biol Chem. 2022;298(11):102568.
Article CAS PubMed PubMed Central Google Scholar
Hsu CW, Lee Y, Lee CY, Lin PY. Neurotoxicity and nephrotoxicity caused by combined use of lithium and risperidone: a case report and literature review. BMC Pharmacol Toxicol. 2016;17(1):59.
Article PubMed PubMed Central Google Scholar
Qiu Y, Sun Y, Xu D, Yang Y, Liu X, Wei Y, et al. Screening of FDA-approved drugs identifies sutent as a modulator of UCP1 expression in brown adipose tissue. EBioMedicine. 2018;37:344–55.
Article PubMed PubMed Central Google Scholar
Qiu Y, Yang Y, Wei Y, Liu X, Feng Z, Zeng X, et al. Glyburide regulates UCP1 expression in Adipocytes Independent of KATP Channel Blockade. iScience. 2020;23(9):101446.
Article CAS PubMed PubMed Central Google Scholar
Xiao W, Xiong Z, Xiong W, Yuan C, Xiao H, Ruan H, et al. Melatonin/PGC1A/UCP1 promotes tumor slimming and represses tumor progression by initiating autophagy and lipid browning. J Pineal Res. 2019;67(4):e12607.
Article CAS PubMed Google Scholar
Qin J, Li R, Raes J, Arumugam M, Burgdorf KS, Manichanh C, et al. A human gut microbial gene catalogue established by metagenomic sequencing. Nature. 2010;464(7285):59–65.
Article CAS PubMed PubMed Central Google Scholar
Moreno-Navarrete JM, Serino M, Blasco-Baque V, Azalbert V, Barton RH, Cardellini M, Latorre J et al. Gut microbiota interacts with markers of adipose tissue Browning, insulin action and plasma acetate in morbid obesity. Mol Nutr Food Res. 2018;62(3).
Li B, Li L, Li M, Lam SM, Wang G, Wu Y, et al. Microbiota Depletion impairs thermogenesis of Brown Adipose tissue and Browning of White Adipose tissue. Cell Rep. 2019;26(10):2720–e27375.
Article CAS PubMed Google Scholar
Li M, Wang S, Li Y, Zhao M, Kuang J, Liang D, et al. Gut microbiota-bile acid crosstalk contributes to the rebound weight gain after calorie restriction in mice. Nat Commun. 2022;13(1):2060.
Article CAS PubMed PubMed Central Google Scholar
Gu Y, Xiao X, Pan R, Zhang J, Zhao Y, Dong Y, Cui H. Lactobacillus plantarum dy-1 fermented barley extraction activates white adipocyte browning in high-fat diet-induced obese rats. J Food Biochem. 2021;45(4):e13680.
Article CAS PubMed Google Scholar
Atarashi K, Suda W, Luo C, Kawaguchi T, Motoo I, Narushima S, et al. Ectopic colonization of oral bacteria in the intestine drives TH1 cell induction and inflammation. Science. 2017;358(6361):359–65.
Article CAS PubMed PubMed Central Google Scholar
Zheng F, Su L, Zhang N, Liu L, Gu J, Du W. Porphyromonas gingivalisderived lipopolysaccharide inhibits brown adipocyte differentiation via lncRNABATE10. Exp Ther Med. 2022;24(6):718.
Article CAS PubMed PubMed Central Google Scholar
Zietak M, Kozak LP. Bile acids induce uncoupling protein 1-dependent thermogenesis and stimulate energy expenditure at thermoneutrality in mice. Am J Physiol Endocrinol Metab. 2016;310(5):E346–54.
Article PubMed Google Scholar
Han Z, Yao L, Zhong Y, Xiao Y, Gao J, Zheng Z, et al. Gut microbiota mediates the effects of curcumin on enhancing Ucp1-dependent thermogenesis and improving high-fat diet-induced obesity. Food Funct. 2021;12(14):6558–75.
Article CAS PubMed Google Scholar
Monfort-Ferré D, Caro A, Menacho M, Martí M, Espina B, Boronat-Toscano A, et al. The Gut Microbiota Metabolite Succinate promotes adipose tissue Browning in Crohn’s Disease. J Crohns Colitis. 2022;16(10):1571–83.
Article PubMed PubMed Central Google Scholar
Pan J, Chui L, Liu T, Zheng Q, Liu X, Liu L, et al. Fecal microbiota was reshaped in UCP1 Knock-In pigs via the adipose-liver-gut Axis and contributed to Less Fat Deposition. Microbiol Spectr. 2023;11(1):e0354022.
Article PubMed Google Scholar
Grujic D, Susulic VS, Harper ME, Himms-Hagen J, Cunningham BA, Corkey BE, Lowell BB. Beta3-adrenergic receptors on white and brown adipocytes mediate beta3-selective agonist-induced effects on energy expenditure, insulin secretion, and food intake. A study using transgenic and gene knockout mice. J Biol Chem. 1997;272(28):17686–93.
Article CAS PubMed Google Scholar
Mineo PM, Cassell EA, Roberts ME, Schaeffer PJ. Chronic cold acclimation increases thermogenic capacity, non-shivering thermogenesis and muscle citrate synthase activity in both wild-type and brown adipose tissue deficient mice. Comp Biochem Physiol Mol Integr Physiol. 2012;161(4):395–400.
Article CAS Google Scholar
de Jong JMA, Sun W, Pires ND, Frontini A, Balaz M, Jespersen NZ, et al. Human brown adipose tissue is phenocopied by classical brown adipose tissue in physiologically humanized mice. Nat Metab. 2019;1(8):830–43.
Article PubMed Google Scholar
Zhang F, Hao G, Shao M, Nham K, An Y, Wang Q, et al. An adipose tissue atlas: an image-guided identification of human-like BAT and Beige depots in rodents. Cell Metab. 2018;27(1):252–e2623.
Article CAS PubMed PubMed Central Google Scholar
Fischer AW, de Jong JMA, Sass F, Schlein C, Heeren J, Petrovic N. Thermoneutrality-Induced Macrophage Accumulation in Brown Adipose tissue does not impair the tissue’s competence for Cold-Induced Thermogenic Recruitment. Front Endocrinol (Lausanne). 2020;11:568682.
Article PubMed Google Scholar
Chang SH, Song NJ, Choi JH, Yun UJ, Park KW. Mechanisms underlying UCP1 dependent and independent adipocyte thermogenesis. Obes Rev. 2019;20(2):241–51.
Article CAS PubMed Google Scholar
Betz MJ, Enerbäck S. Targeting thermogenesis in brown fat and muscle to treat obesity and metabolic disease. Nat Rev Endocrinol. 2018;14(2):77–87.
Article CAS PubMed Google Scholar
Rahbani JF, Bunk J, Lagarde D, et al. Parallel control of cold-triggered adipocyte thermogenesis by UCP1 and CKB. Cell Metab. 2024;36(3):526–e5407.
Article CAS PubMed Google Scholar
Paulo E, Zhang Y, Masand R, Huynh TL, Seo Y, Swaney DL, et al. Brown adipocyte ATF4 activation improves thermoregulation and systemic metabolism. Cell Rep. 2021;36(12):109742.
Article CAS PubMed PubMed Central Google Scholar
Ikeda K, Kang Q, Yoneshiro T, Camporez JP, Maki H, Homma M, et al. UCP1-independent signaling involving SERCA2b-mediated calcium cycling regulates beige fat thermogenesis and systemic glucose homeostasis. Nat Med. 2017;23(12):1454–65.
Article CAS PubMed PubMed Central Google Scholar
Ikeda K, Yamada T. UCP1 dependent and independent thermogenesis in Brown and Beige adipocytes. Front Endocrinol (Lausanne). 2020;11:498.
Article PubMed Google Scholar
Alipoor E, Hosseinzadeh-Attar MJ, Rezaei M, Jazayeri S, Chapman M. White adipose tissue browning in critical illness: a review of the evidence, mechanisms and future perspectives. Obes Rev. 2020;21(12):e13085.
Article PubMed Google Scholar
Ma D, Wu T, Qu Y, Yang J, Cai L, Li X, et al. Astragalus polysaccharide prevents heart failure-induced cachexia by alleviating excessive adipose expenditure in white and brown adipose tissue. Lipids Health Dis. 2023;22(1):9.
Article CAS PubMed PubMed Central Google Scholar
Han YH, Mun JG, Jeon HD, Yoon DH, Choi BM, Kee JY, et al. The Extract of Arctium lappa L. Fruit (Arctii Fructus) improves Cancer-Induced Cachexia by Inhibiting Weight loss of skeletal muscle and adipose tissue. Nutrients. 2020;12(10):3195.
Article CAS PubMed PubMed Central Google Scholar
Cheung WW, Hao S, Wang Z, Ding W, Zheng R, Gonzalez A, et al. Vitamin D repletion ameliorates adipose tissue browning and muscle wasting in infantile nephropathic cystinosis-associated cachexia. J Cachexia Sarcopenia Muscle. 2020;11(1):120–34.
Article PubMed Google Scholar
[Shen Q, Miao CX, Zhang WL, Li YW, Chen QQ, Li XX, et al. SiBaoChongCao exhibited anti-fatigue activities and ameliorated cancer cachexia in mice. RSC Adv. 2019;9(30):17440–56.

Download references

Acknowledgements

Not applicable.

Funding

This work is supported by the National Natural Science Foundation of China (Grant no. 82174037, 81960710) and Yunnan Fundamental Research Projects (Grant no. 202301AS070070, 202307AB110003).

Author information

Dihong Gong and Juanhong Lei contributed equally to this work and should be considered co-first authors.

Authors and Affiliations

Yunnan University of Chinese Medicine, Kunming, 650000, Yunnan, China
Dihong Gong, Juanhong Lei, Xudong He, Junjie Hao, Fan Zhang, Xinya Huang, Wen Gu, Xinxin Yang & Jie Yu

Authors

Dihong Gong
View author publications
You can also search for this author in PubMed Google Scholar
Juanhong Lei
View author publications
You can also search for this author in PubMed Google Scholar
Xudong He
View author publications
You can also search for this author in PubMed Google Scholar
Junjie Hao
View author publications
You can also search for this author in PubMed Google Scholar
Fan Zhang
View author publications
You can also search for this author in PubMed Google Scholar
Xinya Huang
View author publications
You can also search for this author in PubMed Google Scholar
Wen Gu
View author publications
You can also search for this author in PubMed Google Scholar
Xinxin Yang
View author publications
You can also search for this author in PubMed Google Scholar
Jie Yu
View author publications
You can also search for this author in PubMed Google Scholar

Contributions

Dihong gong wrote the main manuscript text and prepared Figs. 1, 2, 3, 4 and 5; Xudong He prepared Figs. 6, 7 and 8; Junjie Hao, Fan Zhang and Wen Gu modified the figures; Xinya Huang, Xinxin Yang and Jie Yu modified the manuscript; All authors reviewed the manuscript.

Corresponding authors

Correspondence to Xinxin Yang or Jie Yu.

Ethics declarations

Ethical approval

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Cite this article

Gong, D., Lei, J., He, X. et al. Keys to the switch of fat burning: stimuli that trigger the uncoupling protein 1 (UCP1) activation in adipose tissue. Lipids Health Dis 23, 322 (2024). https://doi.org/10.1186/s12944-024-02300-z

Download citation

Received: 25 May 2024
Accepted: 14 September 2024
Published: 28 September 2024
DOI: https://doi.org/10.1186/s12944-024-02300-z

Keys to the switch of fat burning: stimuli that trigger the uncoupling protein 1 (UCP1) activation in adipose tissue

Abstract

Introduction

Characterization of UCP1

The structure of UCP1

The function of UCP1

Physical and environmental factors–cold stimulation

Physical and environmental factors–exercises

Factors related to traditional Chinese medicine

Acupuncture

Chinese herbal formulas

Chinese medicinal herbs and their bioactive compounds

Ginseng radix et rhizoma

Coptidis Rhizoma

Zingberis rhizoma recens

Glycyrrhizae radix et rhizoma

Cinnamomi cortex

Menthae Haplocalycis Herba

Others

Functional food and food ingredients

Functional food

Tea

Seeds

Food ingredients

Resveratrol

Anthocyanins

Fucoxanthin

Tea catechins

Capsaicin

Others

Pharmaceutical agents

HMG CoA reductase inhibitors: statins

β3-Adrenoceptor agonists

The PPAR agonist

TRPM8 agonists—Menthol and Icilin

Inhibitors of COX-2

GSK3 inhibitor

Other drugs

The gut microbiota

The strengths and limitations of this review

Conclusion and future perspectives

Data availability

Abbreviations

References

Acknowledgements

Funding

Author information

Authors and Affiliations

Contributions

Corresponding authors

Ethics declarations

Ethical approval

Competing interests

Additional information

Publisher’s note

Rights and permissions

About this article

Cite this article

Share this article

Keywords

Lipids in Health and Disease

Contact us