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

Abstract

The improvement of hepatic insulin sensitivity by the cannabinoid receptor 1 (CB1R) antagonist rimonabant (RIM) has been recently been reported to be due to upregulation of adiponectin. Several studies demonstrated that improvement in insulin clearance accompanies the enhancement of hepatic insulin sensitivity. However, the effects of RIM on hepatic insulin clearance (HIC) have not been fully explored. The aim of this study was to explore the molecular mechanism(s) by which RIM affects HIC, specifically to determine whether upregulation of liver adiponectin receptors (ADRs) and other key genes regulated by adiponectin mediate the effects. To induce insulin resistance in skeletal muscle and liver, dogs were fed a hypercaloric high-fat diet (HFD) for 6 wk. Thereafter, while still maintained on a HFD, animals received RIM (HFDϩRIM; n ϭ 11) or placebo (HFDϩPL; n ϭ 9) for an additional 16 wk. HIC, calculated as the metabolic clearance rate (MCR), was estimated from the euglycemichyperinsulinemic clamp. The HFDϩPL group showed a decrease in MCR; in contrast, the HFDϩRIM group increased MCR. Consistently, the expression of genes involved in HIC, CEACAM-1 and IDE, as well as gene expression of liver ADRs, were increased in the HFDϩRIM group, but not in the HFDϩPL group. We also found a positive correlation between CEACAM-1 and the insulin-degrading enzyme IDE with ADRs. Interestingly, expression of liver genes regulated by adiponectin and involved in lipid oxidation were increased in the HFDϩRIM group. We conclude that in fat-fed dogs RIM enhances HIC, which appears to be linked to an upregulation of the adiponectin pathway. CB1R antagonist; dogs; insulin resistance; insulin clearance; liver THE METABOLIC SYNDROME is a cluster of abnormalities [abdominal obesity, dyslipidemia, hypertension, and nonalcoholic steatohepatitis (NASH)] that are related to insulin resistance and subsequent development of type 2 diabetes. The endocannabinoid system has garnered a great deal of attention as a potential therapeutic target in combating obesity as well as its associated metabolic abnormalities. Compared with their corresponding controls, patients with obesity and type 2 diabetes exhibit higher levels of endocannabinoids in the visceral fat and serum, respectively (32). Chronic treatment with the cannabinoid (CB) receptor (CB1R) antagonist rimonabant (RIM) leads to weight loss and improved insulin sensitivity in obese rodents (15, 43), canines (44), and humans (51). 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). Also, the tremendous increase in cannabinoid intake in the U.S. and elsewhere (10) supports studies of the effects of these agonists and their...

A Peripheral CB1R Antagonist Increases Lipolysis, Oxygen Consumption Rate, and Markers of Beiging in 3T3-L1 Adipocytes Similar to RIM, Suggesting that Central Effects Can Be Avoided

“…The ECS increases uptake and storage of energy by acting through both central and peripheral mechanisms [10]. Chronic treatment with the CB1R antagonist rimonabant (RIM) leads to weight loss and increased insulin sensitivity in multiple models of obesity, including rodents [11,12], canines [13,14], and humans [15]. Weight loss was attributed to decreased fat mass as a result of a reduction in adipocyte cell size in dogs, despite maintenance on a high-fat diet [16].…”

Peripheral modulation of the endocannabinoid system in metabolic disease

“…The beneficial effects of CB1 antagonism in obese patients are attributed in part to an increase of anti-inflammatory and metabo-regulatory adiponectin [165], together with adiponectin receptors [166] in peripheral tissues. Experimental studies confirm a CB1dependent stimulatory effect of endocannabinoids on adipose tissue adiponectin [44,167],…”

Mechanisms of improved glucose handling after metabolic surgery: the big 6

“…This is another example of insulin clearance functioning independently of beta-cell function and shows that insulin clearance is regulated under different mechanisms. In an animal study of high-fat feeding, key regulators in the insulin clearance pathway are altered 36 . Taken together, this further suggests an important, perhaps, causal role for insulin clearance in diabetes progression as well as in remission.…”