Role of adiponectin in the metabolic effects of cannabinoid type 1 receptor blockade in mice with diet-induced obesity

Abstract

The adipocyte-derived hormone adiponectin promotes fatty acid oxidation and improves insulin sensitivity and thus plays a key role in the regulation of lipid and glucose metabolism and energy homeostasis. Chronic cannabinoid type 1 (CB1) receptor blockade also increases lipid oxidation and improves insulin sensitivity in obese individuals or animals, resulting in reduced cardiometabolic risk. Chronic CB1 blockade reverses the obesity-related decline in serum adiponectin levels, which has been proposed to account for the metabolic effects of CB1 antagonists. Here, we investigated the metabolic actions of the CB1 inverse agonist rimonabant in high-fat diet (HFD)-induced obese adiponectin knockout (Adipo(-/-)) mice and their wild-type littermate controls (Adipo(+/+)). HFD-induced obesity and its hormonal/metabolic consequences were indistinguishable in the two strains. Daily treatment of obese mice with rimonabant for 7 days resulted in significant and comparable reductions in body weight, serum leptin, free fatty acid, cholesterol, and triglyceride levels in the two strains. Rimonabant treatment improved glucose homeostasis and insulin sensitivity to the same extent in Adipo(+/+) and Adipo(-/-) mice, whereas it reversed the HFD-induced hepatic steatosis, fibrosis, and hepatocellular damage only in the former. The adiponectin-dependent, antisteatotic effect of rimonabant was mediated by reduced uptake and increased β-oxidation of fatty acids in the liver. We conclude that reversal of the HFD-induced hepatic steatosis and fibrosis by chronic CB1 blockade, but not the parallel reduction in adiposity and improved glycemic control, is mediated by adiponectin.

CB1R antagonist increases hepatic insulin clearance in fat-fed dogs likely via upregulation of liver adiponectin receptors

“…RIM, however, restored SCAD, MCAD, and LCAD levels to those of the Prefat period. Thus, our results are consistent with other studies (13,49) showing that RIM increased fatty acid oxidation in a fat-fed model of insulin resistance. The anti-inflammatory property of adiponectin has been extensively studied in the past decade (38).…”

“…FAS gene expression demonstrated the same tendency. These results are consistent with other studies showing that reversal of HFD-induced hepatic steatosis and fibrosis by RIM requires adiponectin (49). Although this study demonstrated that some hepatoprotective effects of RIM such as improvement of hepatic steatosis and fatty acid oxidation are adiponectin dependent, other metabolic effects, such as decreased improvement of hepatic insulin resistance by RIM, are independent of adiponectin.…”

“…Moreover, several studies have recently shown that RIM has beneficial effects on the liver (14,15). RIM has been shown to reverse steatohepatitis and related features of metabolic syndrome (15,49). Thus, although the commercial cannabinoid receptor antagonist RIM has been withdrawn from the market, it remains important to study the cannabinoid receptor system if additional non-centrally-acting antagonists become available (50).…”

Acute and chronic systemic CB1cannabinoid receptor blockade improves blood pressure regulation and metabolic profile in hypertensive (mRen2)27 rats

“…), and diet‐induced obese mice (Tam et al. ). Similarly, dyslipidemia in the form of elevated triglycerides is reported in (mRen2)27 rats and may contribute to defective insulin signaling in this strain (Sloniger et al.…”

Role of Brown Fat in Lipoprotein Metabolism and Atherosclerosis

“…The effect of these compounds on intestinal lipid absorption remains to be elucidated. Rimonabant enhances FA oxidation in WAT 72 and liver, 73 which could be partly responsible for the lipidlowering effect of rimonabant.…”