CB1 Antagonism Exerts Specific Molecular Effects on Visceral and Subcutaneous Fat and Reverses Liver Steatosis in Diet-Induced Obese Mice

Abstract

OBJECTIVEThe beneficial effects of the inactivation of endocannabinoid system (ECS) by administration of antagonists of the cannabinoid receptor (CB) 1 on several pathological features associated with obesity is well demonstrated, but the relative contribution of central versus peripheral mechanisms is unclear.We examined the impact of CB1 antagonism on liver and adipose tissue lipid metabolism in a mouse model of diet-induced obesity.RESEARCH DESIGN AND METHODSMice were fed either with a standard diet or a high-sucrose high-fat (HSHF) diet for 19 weeks and then treated with the CB1-specific antagonist SR141716 (10 mg · kg−1 · day−1) for 6 weeks.RESULTSTreatment with SR141716 reduced fat mass, insulin levels, and liver triglycerides primarily increased by HSHF feeding. Serum adiponectin levels were restored after being reduced in HSHF mice. Gene expression of scavenger receptor class B type I and hepatic lipase was induced by CB1 blockade and associated with an increase in HDL-cholesteryl ether uptake. Concomitantly, the expression of CB1, which was strongly increased in the liver and adipose tissue of HSHF mice, was totally normalized by the treatment. Interestingly, in visceral but not subcutaneous fat, genes involved in transport, synthesis, oxidation, and release of fatty acids were upregulated by HSHF feeding, while this effect was counteracted by CB1 antagonism.CONCLUSIONSA reduction in the CB1-mediated ECS activity in visceral fat is associated with a normalization of adipocyte metabolism, which may be a determining factor in the reversion of liver steatosis induced by treatment with SR141716.

Transcriptional Regulation of Cannabinoid Receptor-1 Expression in the Liver by Retinoic Acid Acting via Retinoic Acid Receptor-γ

“…Although this effect was unexpected in view of the ability of high levels of cannabinoids to down-regulate CB 1 receptors in the brain, a mechanism of "desensitization" shared by many other ligand/receptor systems, a similar "autoinduction" of CB 1 R by cannabinoids has been reported to occur in T lymphocytes, where the basal levels of CB 1 R expression, similar to hepatocytes, are very low (40). More directly relevant to the present findings is a recent in vivo study in mice, which confirms the up-regulation of hepatic CB 1 R by high fat diet and further reports its complete reversal by chronic treatment with a CB 1 R antagonist (41). This suggests that the CB 1 R autoinduction may also operate under in vivo conditions.…”

Acute cannabinoid receptor type 1 (CB1R) modulation influences insulin sensitivity by an effect outside the central nervous system in mice

“…For example, plasma insulin levels are low in Cb1r −/− mice compared with their wild-type littermates; moreover, the former are resistant to diet-induced obesity and insulin resistance [16]. Plasma insulin levels were reduced in diet-induced obese mice treated with a specific CB1R antagonist SR141716 [13,40]. In rats after chronic treatment with a CB1R antagonist, insulin sensitivity and skeletal muscle glucose uptake were also enhanced, whereas hepatic glucose production was diminished [20].…”

CB1 receptor blockade counters age‐induced insulin resistance and metabolic dysfunction

“…CB1R blockade has also been shown to promote reductions in body fat mass through direct peripheral actions in adipocytes (Jbilo et al ., 2005; Jourdan et al ., 2010). In accord with this, we report the ability of rimonabant to repress or induce lipogenic and lipolytic genes, respectively, in aged epididymal fat tissue.…”

“…Conversely, genetic or pharmacological CB1R blockade improves metabolic status, for example by promoting reductions in body weight and fat mass, as well as enhancing insulin sensitivity and glucose tolerance. Indeed, these beneficial responses may be mediated through central appetite suppression and/or through direct modulation of peripheral energy metabolism (Bensaid et al ., 2003; Ravinet Trillou et al ., 2003, 2004; Jbilo et al ., 2005; Pagotto et al ., 2006; Osei‐Hyiaman et al ., 2008; Jourdan et al ., 2010). …”