The endocannabinoid system (ECS), composed of G-protein-coupled cannabinoid receptors of type 1 and 2 (CB1 and CB2), of endogenous ligands for such receptors, the endocannabinoids arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG), and of enzymes catalysing endocannabinoid biosynthesis and degradation, is a key player in the control of metabolism at both central and peripheral levels . In the hypothalamus, endocannabinoids acting at CB1 receptors modulate the circuitries involved in food intake and are under the negative control of leptin . In the white adipose tissue (WAT), the ECS stimulates lipogenesis and inhibits lipolysis via several mechanisms, and is under the negative control of either leptin or PPARγ [1, 3–5]. PPARγ agonists, such as the glitazones, used for the treatment of type 2 diabetes (T2D), reduce either adipocyte 2-AG concentrations or CB1 receptor expression levels, or both [3–5]. Insulin also acts as a negative modulator of endocannabinoid levels in both human and murine WAT [3, 6, 7]. Plasma endocannabinoid levels, which likely reflect to a large extent the "spill-over" of these lipid mediators from peripheral organs, are decreased postprandially or following oral glucose load and euglycaemic hyperinsulinaemic clamp in lean [3, 8], but not in insulin resistant obese subjects , who, like T2D patients, show higher levels of endocannabinoids also when fasting [3–7, 9].
In abdominally obese individuals, blood 2-AG, but not AEA, concentrations correlate directly with the amount of visceral adipose tissue (VAT) and blood triacylglycerols (TGs), and inversely with HDL-cholesterol levels [10, 11], and such correlations are also observed between the changes in blood 2-AG levels and those in TG and HDL-cholesterol levels induced by a lifestyle intervention leading to a strong reduction of waist circumference and VAT . In experimental models of obesity, higher levels of endocannabinoids are found also in the visceral (e.g. epididymal) vs. subcutaneous adipose depots [3, 13, 14]. This dysregulation of endocannabinoid tone in the WAT is probably due, at least in part, to dysfunctional expression of endocannabinoid metabolising enzymes. In fact, a lower expression of the fatty acid amide hydrolase (FAAH), which can metabolise both AEA and 2-AG, as well as other congeners of AEA (see below), or of the monoacylglycerol lipase (MAGL), which is more specific for 2-AG , has been reported in the VAT of obese individuals [10, 16], possibly accounting for the observed higher VAT levels of 2-AG . As opposed to obese rodents , reduced levels of FAAH expression have been reported for obese subjects also in the subcutaneous adipose tissue (SAT) [9, 16, 17], where, instead, there seems to be no elevation of endocannabinoid levels . However, no such studies have been performed to date in the WAT of obese patients with type 2 diabetes, who can be characterised by similar whole body insulin resistance, but lower plasma leptin levels, as compared to matched non diabetic obese subjects [18, 19].
The SAT plays an important role as a buffer against ectopic lipid accumulation and the subsequent increased inflammatory profile typical of abdominally obese patients . Therefore, in view of the prolipogenic role of the ECS in the WAT, a higher endocannabinoid tone in SAT might be regarded as protective towards the metabolic consequences of obesity, whereas a reduced tone might contribute to these consequences. For this reason, and also to acquire some unprecedented information on endocannabinoid tone in the WAT of subjects with T2D, we have compared here the levels of AEA and 2-AG in the SAT of age- and gender-matched T2D obese (OBT2D), obese only (OB), and normal weight (NW) volunteers. Furthermore, since two cannabinoid receptor-inactive and metabolically-related AEA congeners, oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), which are also degraded by FAAH, are emerging as potent endogenous ligands of peroxisome proliferator-activated receptor α (PPARα), a well established target for the therapy of dyslipidemia , and were recently found to be dysregulated in obese Zucker rats , we have also measured the SAT levels of these two lipid mediators.