- Open Access
A review on the biology and properties of adipose tissue macrophages involved in adipose tissue physiological and pathophysiological processes
Lipids in Health and Disease volume 19, Article number: 164 (2020)
Obesity exhibits a correlation with metabolic inflammation and endoplasmic reticulum stress, promoting the progression of metabolic disease such as diabetes, hyperlipidemia, hyperuricemia and so on. Adipose tissue macrophages (ATMs) are central players in obesity-associated inflammation and metabolic diseases. Macrophages are involved in lipid and energy metabolism and mitochondrial function in adipocytes. Macrophage polarization is accompanied by metabolic shifting between glycolysis and mitochondrial oxidative phosphorylation. Here, this review focuses on macrophage metabolism linked to functional phenotypes with an emphasis on macrophage polarization in adipose tissue physiological and pathophysiological processes. In particular, the interplay between ATMs and adipocytes in energy metabolism, glycolysis, OXPHOS, iron handing and even interactions with the nervous system have been reviewed. Overall, the understanding of protective and pathogenic roles of ATMs in adipose tissue can potentially provide strategies to prevent and treat obesity-related metabolic disorders.
Adipose tissue can be divided into white adipose tissue (WAT) and brown adipose tissue (BAT); the percentage of WAT is up to 5 to 50% of body weight including subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT), and the percentage of BAT decreases with age . Adipose tissue is not only the body’s energy reservoir to insulate against the cold and protect vital organs but also an essential endocrine organ, especially white adipose tissue, which is the main source of endocrine signals .
Macrophages are heterogeneous, and their phenotype and functions are regulated by the surrounding microenvironment . Classically activated M1 or proinflammatory macrophages produce proinflammatory cytokines such as interleukin-1β (IL-1β), IL-6, IL-12, IL-23, and TNF-α, in response to infection and stress. On the other hand, alternatively activated M2 or anti-inflammatory and immunoregulatory macrophages produce anti-inflammatory cytokines such as IL-10 and TGF-β, contribute to tissue repair, remodeling, and vasculogenesis, and maintain homeostasis [4, 5]. Macrophages exploit protective and pathogenic roles in anti-infection defense, antitumor immunity, metabolic disease development, and even obesity .
Adipose tissue macrophages (ATMs) are pivotal players in obesity-associated inflammation and metabolic diseases . Macrophages are key modulators of energy metabolism and mitochondrial function in adipocytes . It seems that ATMs develop from circulating monocytes accumulating in adipose tissue, self-renew from various tissue-resident macrophages , or proliferate in situ driven by monocyte chemotactic protein 1 (MCP-1), which is an important process for macrophages accumulating in VAT in obesity . The number of tissue-infiltrating macrophages is higher in superficial adipose tissue than deep adipose tissue, suggesting accessibility to skin microorganisms might promote macrophage infiltration in SAT . Resident ATMs have lower levels of apoptosis and rapid proliferation during early phases of WAT expansion with a high-fat diet (HFD) [12, 13]. Lipid-rich CD11c+ ATMs appear earlier in VAT than SAT in response to ectopic lipid accumulation as adipocytes reach maximal lipid storage capacity .
The quantity and activation state as well as metabolic phenotype of ATMs impact the development of obesity-induced metabolic diseases. Herein, it is reviewed how ATMs are involved in adipose tissue physiological and pathophysiological processes (Fig. 1).
Macrophage polarization in adipose tissues
Classically activated M1 macrophage polarization
The classically activated M1 macrophages are critical players in the initiation and maintenance of adipose tissue inflammation and progression of insulin resistance in the whole body. Fatty acids and LPS as obesogenic factors activate macrophage inositol-requiring enzyme 1α (IRE1α), which represses M2 while enhancing M1 polarization. The development of obesity and metabolic syndrome is enhanced by the macrophage IRE1α pathway by impairing BAT activity and WAT browning . Excess glucose directly affects macrophage activation via the ROCK/JNK and ROCK/ERK pathways, which induce human monocytes and macrophages to undergo M1 polarization upon exposure to high levels of glucose . miR-30 is downregulated in HFD-induced obesity via DNA methylation, thereby inducing Notch1 signaling in ATMs and promoting M1 macrophage polarization .
Bone-marrow-derived macrophages isolated from Nfatc3−/− mice treated with IFN-γ and lipopolysaccharide resulted in a reduction in M1 inflammatory markers in vitro, suggesting that Nuclear factors of activated T cells (NFAT) c3 promoted M1 polarization in a cell-autonomous way . Fibronectin type III domain-containing protein 5 (FNDC5), a novel myokine secreted by contracting skeletal muscle, can attenuate inflammation and insulin resistance through AMPK-mediated macrophage polarization in HFD-induced obesity .
Alternatively activated M2 macrophage polarization
The alternatively activated M2 macrophages are the predominant macrophage phenotype responsible for anti-inflammation in lean animals. M2 macrophages in adipose tissue inhibited adipocyte progenitor proliferation in the CD206/TGF-β signaling pathway to modulate systemic glucose homeostasis . Deficiency of TLR4 induces the M2-macrophage phenotype and adipose tissue fibrosis . ATMs express NPFFR2, a receptor for the appetite-reducing neuropeptide FF (NPFF), whose plasma levels decrease in obesity, and NPFFR2 deficiency in ATMs abolished both M2 activation and ATM proliferation .
It has been indicated that IL-25 stimulates alternatively activated macrophages and their interaction with adipocytes but promotes energy metabolism, enhances mitochondrial functions and attenuates lipid accumulation in the liver and adipose tissues . In addition, cannabinoid receptor 1 (CB1) blockade resulted in downregulation of miR-466 family and miR-762 in ATMs, which promote M2 polarization and macrophage egress from adipose tissue . Empagliflozin, a sodium-glucose cotransporter (SGLT) 2 inhibitor, repressed weight gain by enhancing browning of adipocytes and alleviated obesity-induced inflammation and insulin resistance by polarizing M2 macrophages in WAT and the liver . Similarly, Telmisartan, a well-known antihypertensive drug, was reported to promote the browning of fully differentiated white adipocytes partly through PPAR-mediated M2 polarization .
Intriguingly, helminth infection significantly alleviated obesity along with significantly increased Th2/Treg responses and M2 macrophage polarization . Adoptive transfer of helminth-stimulated M2 cells to mice without H. polygyrus infection conferred an obvious improvement of HFD-induced obesity and adipose tissue browning . In some cases, an intracellular glucocorticoid reactivating enzyme 11β-HSD1 was found to be in the process of switching ATMs from M2 to mixed M1/M2 polarization .
Adipocytes impact macrophages polarization
Adipocytes exert effects on ATM phenotypes via a variety of mechanisms. HFD upregulates the ER stress pathway downstream component CHOP, a transcription factor C/EBP homologous protein, thereby altering WAT microenvironmental conditions including decreased Th2 cytokine and M1 polarization, resulting in insulin resistance and glucose intolerance . Adipocytes release lipid-laden exosomes (AdExos) that deliver triacylglyceride (TAG) locally to macrophages and are able to induce in vitro differentiation of bone marrow precursors into ATMs . It appears that miR-34a expression is elevated in obesity in part through suppression of the browning activators fibroblast growth factor 21 (FGF21) and SIRT1 to inhibit fat browning . AdExos carried miR-34a into adipose resident macrophages, resulting in repression of the expression of Krüppel-like factor 4 (Klf4) to control M2 polarization . miR-155-bearing adipocyte-derived microvesicles (ADM) can regulate M1 macrophage polarization [32, 33]. However, exosomes derived from adipose-derived stem cells (ADSCs) transactivate argininase-1 to drive M2 macrophage polarization. M2 macrophages further favor the proliferation of ADSC and the browning of adipose tissue by releasing catecholamine, forming a positive feedback loop . The molecular and epigenetic factors that influence macrophages polarization in both physiologic and pathologic wound healing have been reviewed in .
Adipose tissue macrophage subsets with potential functions
Scavenging of adipocyte debris is a crucial function of ATMs in obese individuals. Due to their inability to engulf adipocytes debris in one step, macrophages infiltrate and aggregate in WAT to form a crown-like structure (CLS) that envelopes and ingests the moribund adipocyte at sites of adipocyte death . The tissues are protected from hypoxia and ectopic accumulation from remnant lipid droplet through CLS, which is of extracellular lysosomal compartments . ATMs exert lysosomal activity through two vesicles of different pH. One is a neutral lipid vesicle and the other is an acidic-ringed secondary lysosome involved in lipid catabolism, which is formed by fusion of the first vesicle with the primary lysosome . ATMs localize to CLS with various phenotypes. Moreover, MFe ATMs and antioxidant macrophages (Mox) ATMs are essential to iron and oxidative stress handing, respectively. Furthermore, macrophages polarize in both VAT and subcutaneous abdominal adipose tissue. Hence, multiple ATM phenotypes with potential functions have been reviewed in [Table 1].
Macrophages in a crown-like structure of adipose tissues
ATMs adopt a metabolically activated (MMe) phenotype to eliminate dead adipocytes in the way of lysosomal exocytosis . In contrast to classically activated macrophages expressing cell surface markers such as CD38, CD319, and CD274, MMe macrophages specifically overexpress ABCA1, CD36, and PLIN2 regulated by p62 and PPARγ . Recently, it has been revealed that MMe macrophages release IL-6 in an NADPH oxidase 2 (NOX2)-dependent manner, which signals through glycoprotein 130 (GP130) on triple-negative breast cancer (TNBC) cells to promote stem-like properties including tumor formation . MMe macrophages exhibit a pleiotropic effect on tissue environmental homeostasis, which can cause corresponding pathophysiological changes to vary with the progression of obesity. NADPH oxidase 2 (NOX2) has been identified as a driver of the inflammatory and adipocyte-clearing properties of MMe macrophages. Nox2−/− mice show mildly improved glucose tolerance in early diet-induced obesity (DIO) compared with wild-type mice due to decreased secretion of inflammatory factors . However, when advanced to late DIO, inactivation of the lysosomal exocytosis function would result in tissue damage due to from severe lipid accumulation .
CD9+ ATMs, which are lipid-laden and localized to CLSs, are responsible for the inflammatory signature of obese adipose tissue, and adoptive transfer of CD9+ ATMs induces obese-associated inflammation in lean mice . CD9+ ATMs express higher levels of the surface markers CD16 and CD206 than CD9− ATMs and are enriched for transcription factors AP-1 and NF-κB with associated genes such as Ccl2, Il1a, Il18, and Tnf . In contrast to CD9 ATMs with a signature of metabolic activation, Ly6c ATMs express genes related to angiogenesis and tissue organization. Ly6c ATMs provide normal adipose physiology upon adoptive transfer by inducing genes related to cholesterol and lipid biosynthesis .
Recently, a novel and conserved macrophage named lipid-associated macrophage (LAM) with high levels of the lipid receptor Trem2 has been proven to be the predominantly expanded immune cell subset in adipose tissue in multiple obesity-related mouse models . The formation of LAM cells in CLS in adipose tissue is driven by Trem2 signaling, and knockout of Trem2 in bone marrow cells deteriorated the metabolic outcomes of obesity, suggesting that Trem2+ LAM cells are crucial for the prevention of metabolic disorders upon loss of adipose tissue homeostasis .
Iron-rich macrophages in adipose tissues
A study describes a novel population of alternatively activated iron-rich ATMs named MFehi, which display an anti-inflammatory and iron-recycling gene expression profile . MFehi ATMs are capable of storing excess iron from dietary and intraperitoneal supplements mainly through MFelo ATM incorporation to expand the MFehi pool . The impaired iron handling in MFehi ATMs has impacted iron distribution, causing adipocyte iron overload and AT dysfunction in obesity . Compared with LFD-fed mice, HFD-feeding increased Itgax, Ccr7, Tnfα and Il1β expression and decreased M2 marker expression of Stab1 and Clec10a in MFehi ATMs .
Antioxidant macrophages in adipose tissues
Oxidized phospholipids (OxPLs) have been identified as endogenous danger associated molecular patterns (DAMPs) with characteristics of oxidative damage to tissues. Macrophages have the capacity to translate tissue oxidation status into either antioxidant or inflammatory responses by sensing OxPLs . Antioxidant macrophages (Mox) respond to OxPLs by upregulating Nrf2-dependent antioxidant enzymes  and producing the antioxidant glutathione to suppress regular energy metabolism . A unique population of CX3CR1neg/F4/80low ATMs that resemble the Mox phenotype (Txnrd1+HO1+) has been demonstrated to be the predominant ATMs in lean adipose tissue .
Macrophages in visceral adipose tissues and subcutaneous adipose tissues
Macrophage polarization in human visceral adipose tissue is related to fatty acid metabolism, cell membrane composition, and diet. CD11c+CD163+ ATMs have been confirmed to accumulate in both VAT and SAT of obese individuals and were found to be clearly correlated with body mass index and production of reactive oxygen species . Proinflammatory and anti-inflammatory macrophages from human VAT have been determined by flow cytometry as CD14+CD16+CD36high and CD14+CD16−CD163+, respectively . Macrophages in obese adipose tissue are CD11c+CD206+, interpreted to be hybrid M1/M2 macrophages .
Other adipose tissue macrophages
Macrophages exhibit correlations with adipocyte accumulation in human skeletal muscles. IL-1β-polarized macrophages (M(IL-1β)) drastically reduced fibroadipogenic progenitors (FAP) adipogenic potential, while IL-4-polarized macrophages (M(IL-4)) enhanced FAP adipogenesis . Tissue-resident NRP1+ macrophages can drive healthy weight gain and maintain glucose tolerance. Ablation of NRP1 in macrophages compromised lipid uptake in these cells, which reduced substrates for fatty acid β-oxidation and shifted energy metabolism of these macrophages toward a more inflammatory glycolytic metabolism .
Macrophages and adipocytes interact in physiological and pathological events
White adipose tissue serves as an energy-storage organ and plays a homeostatic role in energy dissipation . Moreover, brown adipose tissue generates heat through uncoupled respiration, protecting against hypothermia, hyperglycemia and hyperlipidemia [54, 55]. In addition, beige adipocytes inducibly express mitochondrial uncoupling protein UCP1 in response to cold exposure and execute a thermogenic and energy-dissipating function interspersed within white adipose tissue .
Macrophage-adipocyte interaction in energy metabolism
It has been reported that brown adipocytes release CXCL14 to promote adaptive thermogenesis via M2 macrophage recruitment, BAT activation and white fat browning . Likewise, it has been identified that ATM-generated miR-10a-5p is a potential regulator of inflammation in ATMs and induces beige adipogenesis in adipocyte stem cells (ASCs) . Currently, it has been delineated that alkylglycerol-type ether lipids (AKGs) such as breast milk-specific lipid species are metabolized by ATMs to platelet-activating factor (PAF), which ultimately activates IL-6/STAT3 signaling in adipocytes and triggers beige adipose tissue development in infants . In contrast, the partial depletion of CD206+ M2 macrophages elevates the number of beige progenitors in response to cold in genetically engineered CD206DTR mice . M1 macrophages may be partially associated with failure in perigonadal WAT that undergoes browning, as evidenced by removal of macrophages enhancing cold-induced UCP1 expression .
Additionally, inflammatory macrophages adhere to adipocytes, mediated by α4 integrin binding to VCAM-1, inhibiting thermogenic UCP1 expression in an Erk-dependent way, thereby impairing beige adipogenesis in obesity . Furthermore, macrophages modulate energy metabolism of WAT in an activation-dependent paracrine way, as evidenced by how CD163highCD40low macrophages activated by IL-10/TGF-β downregulated the expression of mitochondrial complex III (UQCRC2) gene/protein and ATP-linked respiration, whereas CD40highCD163low macrophages activated by LPS/IFN-γ potentiated adipocyte mitochondrial activity .
In addition, JAK2, a key mediator downstream of various cytokines and growth factors, which is deficient in macrophages, improves systemic insulin sensitivity and reduces inflammation in VAT and liver in response to metabolic stress . The nuclear lamina is a protein network structure surrounding the nuclear material that participates in a number of intranuclear reactions. Lamin A/C mediates ATM inflammation by activating NF-κB to promote proinflammatory gene expression, hence hastening obesity-associated insulin resistance .
Macrophage-adipocyte interaction in glycolysis and OXPHOS
Growing evidence has shown that ATMs adopt a unique metabolic profile such as glycolysis and oxidative phosphorylation (OXPHOS), while fatty acid oxidation, glycolysis and glutaminolysis have been reported to facilitate ATMs to release cytokine in lean adipose tissue . Inflammatory macrophages (M1) have metabolic features such as increased succinate-driven Hif1α-dependent glycolysis  and reduced phosphorylation, as well as a TCA cycle break-point at Idh . On the other hand, anti-inflammatory macrophages (M2) possess characteristics such as enhanced OXPHOS, UDP-GlcNAc biosynthesis and glutamine-related pathway flows . Cpt2A−/− mice in which mitochondrial long chain fatty acid β-oxidation was deleted were induced to undergo loss of BAT and a reduction in UCP1 expression by administration of β3-adrenergic (CL-316243) or thyroid hormone (GC-1) agonists, suggesting that adipose fatty acid oxidation is required for the development of BAT during both activation and quiescence .
Release of succinate by adipose tissue is a response to hypoxia and hyperglycemia. Succinate receptor 1 (SUCNR1) activation mediates macrophage infiltration and inflammation in obesity, as evidenced by how Sucnr1−/− mice displayed decreased macrophage numbers and increased glucose tolerance . Adipose tissue hypoxia impact on preadipocytes and ATMs in obesity has been reviewed in detail in reference .
Macrophages, adipocytes and nervous system
The interplay between neuroimmunology and immunometabolism is prevalent within adipose tissue, where immune cells and the sympathetic nervous system play a critical role in metabolic homeostasis and obesity . The interaction between neurons and macrophages has influenced adipocyte biology and whole-body metabolism . Although alternatively activated macrophages do not synthesize relevant amounts of catecholamines , a recent study has shown that Irs2LyzM−/− mice are resistant to obesity upon HFD-feeding via regulation of sympathetic nerve function and catecholamine availability in adipose tissue to activate BAT and beigeing of WAT . Macrophages deficient in Irs2 express an anti-inflammatory profile and catecholamine scavenging associated genes to support adipose tissue sympathetic innervation .
It has been supposed that neuron-associated macrophages (SAMs) pathologically accumulate in sympathetic nervous system (SNS) nerves of obese subjects in an organ-specific manner, acting as a norepinephrine (NE) sink and exerting proinflammatory activity . Deletion of Mecp2 in CX3CR1+ macrophages impeded BAT sympathetic innervation, disrupting NE signaling required for expression of uncoupling protein 1 (UCP1) and BAT thermogenesis . The impairment of catecholamine-induced lipolysis in aging was reversed by alteration of the expression of NLRP3, growth differentiation factor-3(GDF3) and monoamine oxidase A (MAOA) in AT macrophages via regulating the bioavailability of noradrenaline .
Macrophage-adipocyte interactions in other aspects
The adipose tissue microenvironment interrupts late autophagosome maturation in macrophages, supporting enhanced lipid-droplet (LD) biogenesis and AT foam cell (FC) formation, thereby contributing to AT dysfunction in obesity . Growth/differentiation factor 3 (GDF3) is an activin receptor-like kinase 7 (ALK7) ligand produced from CD11c+ macrophages to control lipolysis and direct ALK7-dependent accumulation of fat in vivo. It has been clarified that the GDF3-ALK7 axis between macrophages and adipocytes is tied to insulin regulation of both fat metabolism and mass . Antigen presentation by either ATMs or adipocytes must be preserved in order to improve systemic glucose metabolism in HFD-fed mice . Specific loss of APC function in ATMs yields mice that are more glucose tolerant. APC function loss in either ATMs or adipocytes, but not both, improves systemic glucose metabolism .
ATMs responsible for immune surveillance in adipose tissue during HFD-induced obesity are reprogrammed to produce inflammatory and metabolic activated subsets. In addition to M1 and M2 subsets, ATMs with a variety of cell phenotypes to perform their roles in clearance of cellular debris, lipid metabolism, iron storage and energy metabolism in both physiological and pathological states. In summary, the current understanding of the characteristics of the biology and properties of macrophages in adipose tissues facilitates the elucidation of ATM polarization, metabolism and regulatory mechanisms. Fully exploration of ATMs functions in obesity can provide potential pharmacologic control points to prevent and treat obesity-related metabolic disorders. Furthermore, the microenvironment of adipose tissues in obesity needs further investigation, especially the epigenetic and transcriptional regulation of the physiological changes of adipocytes from the interplay between ATMs and adipocytes.
Availability of data and materials
Adipose tissue macrophages
Adipose-derived stem cells
Adipocyte stem cells
Alkylglycerol-type ether lipids
Activin receptor-like kinase 7
Adipocytes release lipid-laden exosomes
Brown adipose tissue
Cannabinoid receptor 1
C/EBP homologous protein
deep Adipose tissue
Danger associated molecular patterns
Fibronectin type III domain-containing protein 5
Fibroblast growth factor 21
Growth/differentiation factor 3
Inositol-requiring enzyme 1α
Krüppel-like factor 4
Monocyte chemotactic protein 1
- Mox ATMs:
Metabolically activated phenotype
Classically activated macrophages
Alternatively activated macrophages
- NFAT c3:
NUCLEAR factors of activated T cells c3
NADPH oxidase 2
Subcutaneous adipose tissue
Succinate receptor 1
Sympathetic nervous system
Triple-negative breast cancer
Uncoupling protein 1
Unfolded protein reactions
Visceral adipose tissue
White adipose tissue
Ibrahim MM. Subcutaneous and visceral adipose tissue: structural and functional differences. Obes Rev. 2010;11(1):11–8.
O'Rourke RW. Adipose tissue and the physiologic underpinnings of metabolic disease. Surg Obes Relat Dis. 2018;14(11):1755–63.
Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233(9):6425–40.
Mills CD. Anatomy of a discovery: m1 and m2 macrophages. Front Immunol. 2015;6:212.
Wang Y, Smith W, Hao D, He B, Kong L. M1 and M2 macrophage polarization and potentially therapeutic naturally occurring compounds. Int Immunopharmacol. 2019;70:459–66.
Gordon S, Martinez-Pomares L. Physiological roles of macrophages. Pflugers Arch. 2017;469(3–4):365–74.
Cinkajzlova A, Mraz M, Haluzik M. Lymphocytes and macrophages in adipose tissue in obesity: markers or makers of subclinical inflammation? Protoplasma. 2017;254(3):1219–32.
Russo L, Lumeng CN. Properties and functions of adipose tissue macrophages in obesity. Immunology. 2018;155(4):407–17.
Hassnain Waqas SF, Noble A, Hoang AC, Ampem G, Popp M, Strauss S, et al. Adipose tissue macrophages develop from bone marrow-independent progenitors in Xenopus laevis and mouse. J Leukoc Biol. 2017;102(3):845–55.
Amano SU, Cohen JL, Vangala P, Tencerova M, Nicoloro SM, Yawe JC, et al. Local proliferation of macrophages contributes to obesity-associated adipose tissue inflammation. Cell Metab. 2014;19(1):162–71.
Cappellano G, Morandi EM, Rainer J, Grubwieser P, Heinz K, Wolfram D, et al. Human macrophages preferentially infiltrate the superficial adipose tissue. Int J Mol Sci. 2018;19(5):1404.
Zamarron BF, Mergian TA, Cho KW, Martinez-Santibanez G, Luan D, Singer K, et al. Macrophage proliferation sustains adipose tissue inflammation in formerly obese mice. Diabetes. 2017;66(2):392–406.
Muir LA, Kiridena S, Griffin C, DelProposto JB, Geletka L, Martinez-Santibanez G, et al. Frontline Science: Rapid adipose tissue expansion triggers unique proliferation and lipid accumulation profiles in adipose tissue macrophages. J Leukoc Biol. 2018;103(4):615–28.
Shan B, Wang X, Wu Y, Xu C, Xia Z, Dai J, et al. The metabolic ER stress sensor IRE1alpha suppresses alternative activation of macrophages and impairs energy expenditure in obesity. Nat Immunol. 2017;18(5):519–29.
Torres-Castro I, Arroyo-Camarena UD, Martinez-Reyes CP, Gomez-Arauz AY, Duenas-Andrade Y, Hernandez-Ruiz J, et al. Human monocytes and macrophages undergo M1-type inflammatory polarization in response to high levels of glucose. Immunol Lett. 2016;176:81–9.
Miranda K, Yang X, Bam M, Murphy EA, Nagarkatti PS, Nagarkatti M. MicroRNA-30 modulates metabolic inflammation by regulating notch signaling in adipose tissue macrophages. Int J Obes. 2018;42(6):1140–50.
Hu L, He F, Huang M, Peng M, Zhou Z, Liu F, et al. NFATc3 deficiency reduces the classical activation of adipose tissue macrophages. J Mol Endocrinol. 2018;61(3):79–89.
Xiong XQ, Geng Z, Zhou B, Zhang F, Han Y, Zhou YB, et al. FNDC5 attenuates adipose tissue inflammation and insulin resistance via AMPK-mediated macrophage polarization in obesity. Metabolism. 2018;83:31–41.
Nawaz A, Aminuddin A. CD206(+) M2-like macrophages regulate systemic glucose metabolism by inhibiting proliferation of adipocyte progenitors. Nat Commun. 2017;8(1):286.
Griffin C, Eter L, Lanzetta N, Abrishami S, Varghese M, McKernan K, et al. TLR4, TRIF, and MyD88 are essential for myelopoiesis and CD11c(+) adipose tissue macrophage production in obese mice. J Biol Chem. 2018;293(23):8775–86.
Waqas SFH, Hoang AC, Lin YT, Ampem G, Azegrouz H, Balogh L, et al. Neuropeptide FF increases M2 activation and self-renewal of adipose tissue macrophages. J Clin Invest. 2017;127(9):3559.
Feng J, Li L, Ou Z, Li Q, Gong B, Zhao Z, et al. IL-25 stimulates M2 macrophage polarization and thereby promotes mitochondrial respiratory capacity and lipolysis in adipose tissues against obesity. Cell Mol Immunol. 2018;15(5):493–505.
Mehrpouya-Bahrami P, Miranda K, Singh NP, Zumbrun EE, Nagarkatti M, Nagarkatti PS. Role of microRNA in CB1 antagonist-mediated regulation of adipose tissue macrophage polarization and chemotaxis during diet-induced obesity. J Biol Chem. 2019;294(19):7669–81.
Xu L, Nagata N, Nagashimada M, Zhuge F, Ni Y, Chen G, et al. SGLT2 inhibition by Empagliflozin promotes fat utilization and Browning and Attenuates inflammation and insulin resistance by polarizing M2 macrophages in diet-induced obese mice. EBioMedicine. 2017;20:137–49.
Jeon EJ, Kim DY, Lee NH, Choi HE, Cheon HG. Telmisartan induces browning of fully differentiated white adipocytes via M2 macrophage polarization. Sci Rep. 2019;9(1):1236.
Su CW, Chen CY, Li Y, Long SR, Massey W, Kumar DV, et al. Helminth infection protects against high fat diet-induced obesity via induction of alternatively activated macrophages. Sci Rep. 2018;8(1):4607.
Nakajima S, Koh V, Kua LF, So J, Davide L, Lim KS, et al. Accumulation of CD11c+CD163+ adipose tissue macrophages through Upregulation of intracellular 11beta-HSD1 in human obesity. J Immunol. 2016;197(9):3735–45.
Suzuki T, Gao J, Ishigaki Y, Kondo K, Sawada S, Izumi T, et al. ER stress protein CHOP mediates insulin resistance by modulating adipose tissue macrophage polarity. Cell Rep. 2017;18(8):2045–57.
Flaherty SE 3rd, Grijalva A, Xu X, Ables E, Nomani A. A lipase-independent pathway of lipid release and immune modulation by adipocytes. Science. 2019;363(6430):989–93.
Fu T, Seok S, Choi S, Huang Z, Suino-Powell K, Xu HE, et al. MicroRNA 34a inhibits beige and brown fat formation in obesity in part by suppressing adipocyte fibroblast growth factor 21 signaling and SIRT1 function. Mol Cell Biol. 2014;34(22):4130–42.
Pan Y, Hui X, Hoo RLC, Ye D, Chan CYC, Feng T, et al. Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation. J Clin Invest. 2019;129(2):834–49.
Zhang Y, Mei H, Chang X, Chen F, Zhu Y, Han X. Adipocyte-derived microvesicles from obese mice induce M1 macrophage phenotype through secreted miR-155. J Mol Cell Biol. 2016;8(6):505–17.
Ying W, Riopel M, Bandyopadhyay G, Dong Y, Birmingham A, Seo JB, et al. Adipose tissue macrophage-derived Exosomal miRNAs can modulate in vivo and in vitro insulin sensitivity. Cell. 2017;171(2):372–84.
Zhao H, Shang Q, Pan Z, Bai Y, Li Z, Zhang H, et al. Exosomes from adipose-derived stem cells attenuate adipose inflammation and obesity through polarizing M2 macrophages and Beiging in white adipose tissue. Diabetes. 2018;67(2):235–47.
Boniakowski AE, Kimball AS, Jacobs BN, Kunkel SL, Gallagher KA. Macrophage-mediated inflammation in Normal and diabetic wound healing. J Immunol. 2017;199(1):17–24.
Cinti S, Mitchell G, Barbatelli G, Murano I, Ceresi E, Faloia E, et al. Adipocyte death defines macrophage localization and function in adipose tissue of obese mice and humans. J Lipid Res. 2005;46(11):2347–55.
Kratz M, Coats BR, Hisert KB, Hagman D, Mutskov V, Peris E, et al. Metabolic dysfunction drives a mechanistically distinct proinflammatory phenotype in adipose tissue macrophages. Cell Metab. 2014;20(4):614–25.
Tiwari P, Blank A, Cui C, Schoenfelt KQ, Zhou G, Xu Y, et al. Metabolically activated adipose tissue macrophages link obesity to triple-negative breast cancer. J Exp Med. 2019;216(6):1345–58.
Xu X, Grijalva A, Skowronski A, van Eijk M, Serlie MJ, Ferrante AW Jr. Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation. Cell Metab. 2013;18(6):816–30.
Hill DA, Lim HW, Kim YH, Ho WY, Foong YH, Nelson VL, et al. Distinct macrophage populations direct inflammatory versus physiological changes in adipose tissue. Proc Natl Acad Sci U S A. 2018;115(22):E5096–e105.
Nikolic T, Movita D, Lambers ME, Ribeiro de Almeida C, Biesta P, Kreefft K, et al. The DNA-binding factor Ctcf critically controls gene expression in macrophages. Cell Mol Immunol. 2014;11(1):58–70.
Orr JS, Kennedy A, Anderson-Baucum EK, Webb CD, Fordahl SC, Erikson KM, et al. Obesity alters adipose tissue macrophage iron content and tissue iron distribution. Diabetes. 2014;63(2):421–32.
Hubler MJ, Erikson KM, Kennedy AJ, Hasty AH. MFe (hi) adipose tissue macrophages compensate for tissue iron perturbations in mice. Am J Physiol Cell Physiol. 2018;315(3):C319–c29.
Serbulea V, Upchurch CM, Schappe MS, Voigt P, DeWeese DE, Desai BN, et al. Macrophage phenotype and bioenergetics are controlled by oxidized phospholipids identified in lean and obese adipose tissue. Proc Natl Acad Sci U S A. 2018;115(27):E6254–E63.
Kadl A, Meher AK, Sharma PR, Lee MY, Doran AC, Johnstone SR, et al. Identification of a novel macrophage phenotype that develops in response to atherogenic phospholipids via Nrf2. Circ Res. 2010;107(6):737–46.
Serbulea V, Upchurch CM, Ahern KW, Bories G, Voigt P, DeWeese DE, et al. Macrophages sensing oxidized DAMPs reprogram their metabolism to support redox homeostasis and inflammation through a TLR2-Syk-ceramide dependent mechanism. Mol Metab. 2018;7:23–34.
Wentworth JM, Naselli G, Brown WA, Doyle L, Phipson B, Smyth GK, et al. Pro-inflammatory CD11c+CD206+ adipose tissue macrophages are associated with insulin resistance in human obesity. Diabetes. 2010;59(7):1648–56.
Poledne R, Malinska H, Kubatova H, Fronek J, Thieme F, Kauerova S, et al. Polarization of macrophages in human adipose tissue is related to the fatty acid Spectrum in membrane phospholipids. Nutrients. 2019;12(1):8.
Coats BR, Schoenfelt KQ, Barbosa-Lorenzi VC, Peris E, Cui C, Hoffman A, et al. Metabolically activated adipose tissue macrophages perform detrimental and beneficial functions during diet-induced obesity. Cell Rep. 2017;20(13):3149–61.
Jaitin DA, Adlung L, Thaiss CA, Weiner A, Li B, Descamps H, et al. Lipid-associated macrophages control metabolic homeostasis in a Trem2-dependent manner. Cell. 2019;178(3):686–98.
Moratal C, Raffort J, Arrighi N, Rekima S, Schaub S, Dechesne CA, et al. IL-1beta- and IL-4-polarized macrophages have opposite effects on adipogenesis of intramuscular fibro-adipogenic progenitors in humans. Sci Rep. 2018;8(1):17005.
Wilson AM, Shao Z, Grenier V, Mawambo G, Daudelin J-F, Dejda A, et al. Neuropilin-1 expression in adipose tissue macrophages protects against obesity and metabolic syndrome. Sci Immunol. 2018;3(21):eaan4626.
Montanari T, Poscic N, Colitti M. Factors involved in white-to-brown adipose tissue conversion and in thermogenesis: a review. Obes Rev. 2017;18(5):495–513.
Betz MJ, Enerback S. Human Brown adipose tissue: what we have learned So far. Diabetes. 2015;64(7):2352–60.
Bargut TC, Aguila MB, Mandarim-de-Lacerda CA. Brown adipose tissue: updates in cellular and molecular biology. Tissue Cell. 2016;48(5):452–60.
Wu J, Bostrom 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.
Cereijo R, Gavalda-Navarro A, Cairo M, Quesada-Lopez T, Villarroya J, Moron-Ros S, et al. CXCL14, a Brown Adipokine that mediates Brown-fat-to-macrophage communication in Thermogenic adaptation. Cell Metab. 2018;28(5):750–63.
Cho YK, Son Y, Kim SN, Song HD, Kim M, Park JH, et al. MicroRNA-10a-5p regulates macrophage polarization and promotes therapeutic adipose tissue remodeling. Mol Metab. 2019;29:86–98.
Yu H, Dilbaz S, Cossmann J, Hoang AC, Diedrich V, Herwig A, et al. Breast milk alkylglycerols sustain beige adipocytes through adipose tissue macrophages. J Clin Invest. 2019;129(6):2485–99.
Igarashi Y, Nawaz A, Kado T, Bilal M, Kuwano T, Yamamoto S, et al. Partial depletion of CD206-positive M2-like macrophages induces proliferation of beige progenitors and enhances browning after cold stimulation. Sci Rep. 2018;8(1):14567.
Machida K, Okamatsu-Ogura Y, Shin W, Matsuoka S, Tsubota A, Kimura K. Role of macrophages in depot-dependent browning of white adipose tissue. J Physiol Sci. 2018;68(5):601–8.
Chung KJ, Chatzigeorgiou A, Economopoulou M, Garcia-Martin R, Alexaki VI, Mitroulis I, et al. A self-sustained loop of inflammation-driven inhibition of beige adipogenesis in obesity. Nat Immunol. 2017;18(6):654–64.
Keuper M, Sachs S, Walheim E, Berti L, Raedle B, Tews D, et al. Activated macrophages control human adipocyte mitochondrial bioenergetics via secreted factors. Mol Metab. 2017;6(10):1226–39.
Desai HR, Sivasubramaniyam T, Revelo XS, Schroer SA, Luk CT, Rikkala PR, et al. Macrophage JAK2 deficiency protects against high-fat diet-induced inflammation. Sci Rep. 2017;7(1):7653.
Kim Y, Bayona PW, Kim M, Chang J, Hong S, Park Y, et al. Macrophage Lamin a/C regulates inflammation and the development of obesity-induced insulin resistance. Front Immunol. 2018;9:696.
Boutens L, Hooiveld GJ, Dhingra S, Cramer RA, Netea MG, Stienstra R. Unique metabolic activation of adipose tissue macrophages in obesity promotes inflammatory responses. Diabetologia. 2018;61(4):942–53.
Jha AK, Huang SC, Sergushichev A, Lampropoulou V, Ivanova Y, Loginicheva E, et al. Network integration of parallel metabolic and transcriptional data reveals metabolic modules that regulate macrophage polarization. Immunity. 2015;42(3):419–30.
Gonzalez-Hurtado E, Lee J, Choi J, Wolfgang MJ. Fatty acid oxidation is required for active and quiescent brown adipose tissue maintenance and thermogenic programing. Mol Metab. 2018;7:45–56.
van Diepen JA, Robben JH, Hooiveld GJ, Carmone C, Alsady M, Boutens L, et al. SUCNR1-mediated chemotaxis of macrophages aggravates obesity-induced inflammation and diabetes. Diabetologia. 2017;60(7):1304–13.
Engin A. Adipose tissue hypoxia in obesity and its impact on Preadipocytes and macrophages: hypoxia hypothesis. Adv Exp Med Biol. 2017;960:305–26.
Larabee CM, Neely OC, Domingos AI. Obesity: a neuroimmunometabolic perspective. Nat Rev Endocrinol. 2020;16(1):30–43.
Boura-Halfon S, Pecht T, Jung S, Rudich A. Obesity and dysregulated central and peripheral macrophage-neuron cross-talk. Eur J Immunol. 2019;49(1):19–29.
Fischer K, Ruiz HH, Jhun K, Finan B, Oberlin DJ, van der Heide V, et al. Alternatively activated macrophages do not synthesize catecholamines or contribute to adipose tissue adaptive thermogenesis. Nat Med. 2017;23(5):623–30.
Rached MT, Millership SJ, Pedroni SMA, Choudhury AI, Costa ASH, Hardy DG, et al. Deletion of myeloid IRS2 enhances adipose tissue sympathetic nerve function and limits obesity. Mol Metab. 2019;20:38–50.
Pirzgalska RM, Seixas E, Seidman JS, Link VM, Sanchez NM, Mahu I, et al. Sympathetic neuron-associated macrophages contribute to obesity by importing and metabolizing norepinephrine. Nat Med. 2017;23(11):1309–18.
Wolf Y, Boura-Halfon S, Cortese N, Haimon Z, Sar Shalom H, Kuperman Y, et al. Brown-adipose-tissue macrophages control tissue innervation and homeostatic energy expenditure. Nat Immunol. 2017;18(6):665–74.
Camell CD, Sander J, Spadaro O, Lee A, Nguyen KY, Wing A, et al. Inflammasome-driven catecholamine catabolism in macrophages blunts lipolysis during ageing. Nature. 2017;550(7674):119–23.
Bechor S, Nachmias D, Elia N, Haim Y, Vatarescu M, Leikin-Frenkel A, et al. Adipose tissue conditioned media support macrophage lipid-droplet biogenesis by interfering with autophagic flux. Biochim Biophys Acta Mol Cell Biol Lipids. 2017;1862(9):1001–12.
Bu Y, Okunishi K, Yogosawa S, Mizuno K, Irudayam MJ, Brown CW, et al. Insulin regulates lipolysis and fat mass by Upregulating growth/differentiation factor 3 in adipose tissue macrophages. Diabetes. 2018;67(9):1761–72.
Blaszczak AM, Wright VP, Anandani K, Liu J, Jalilvand A, Bergin S, et al. Loss of antigen presentation in adipose tissue macrophages or in adipocytes, but not both. Improves Glucose Metab J Immunol. 2019;202(8):2451–9.
This manuscript was supported with grants from Liaoning Province Natural Science Foundation Guidance Program 2019-ZD-0795 (RQM), Liaoning Province College Students’ Innovation and Entrepreneurship Project 201910159209 (RQM), and Liaoning Province College Students’ Innovation and Entrepreneurship Project 201910159033 (YJL and KY).
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Li, Y., Yun, K. & Mu, R. A review on the biology and properties of adipose tissue macrophages involved in adipose tissue physiological and pathophysiological processes. Lipids Health Dis 19, 164 (2020). https://doi.org/10.1186/s12944-020-01342-3
- Adipose tissue macrophages
- White adipose tissue
- Brown adipose tissue
- Beige adipose tissue
- Lipid metabolism
- Energy metabolism
- Metabolic disorders