Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice

Abstract

Effect of peripheral cannabinoid receptor 1 (CB1R) blockade by AM6545 in the monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity was observed, and the impact on intraperitoneal adipose tissue and adipokines was investigated. The MSG mice is characterized by excessive abdominal obesity, and combined with dyslipidemia and insulin resistance. 3-Week AM6545 treatment dose-dependently decreased the body weight, intraperitoneal fat mass, and rectified the accompanied dyslipidemia include elevated serum triglyceride, total cholesterol, free fatty acids, and lowered LDLc level. Glucose intolerance and hyperinsulinemia were also alleviated. But AM6545 didn’t affect the food-intake consistently through the experiment. In line with the reduction on fat mass, the size of adipocyte was reduced markedly. Most interestingly, AM6545 showed significant improvement on levels of circulating adipokines including lowering leptin, asprosin and TNFα, and increasing HMW adiponectin. Correspondingly, dysregulated gene expression of lipogenesis, lipolysis, and adipokines in the adipose tissue were nearly recovered to normal level after AM6545 treatment. Additionally, western blot analysis revealed that AM6545 corrected the elevated CB1R and PPARγ protein expression, while increased the key energy uncoupling protein UCP1 expression in adipose tissue. Taken together, the current study indicates that AM6545 induced a comprehensive metabolic improvement in the MSG mice including counteracting the hypometabolic and hypothalamic obesity, and improving the accompanied dyslipidemia and insulin resistance. One key underlying mechanism is related to ameliorate on the metabolic deregulation of adipose tissue, the synthesis and secretion of adipokines were thus rectified, and finally the catabolism was increased and the anabolism was reduced in intraperitoneal adipose tissue. Findings from this study will provide the valuable information about peripheral CB1R antagonist in managing hypometabolic obesity.

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

“…Taken together, our results reveal that peripheral CB1R antagonist AM6545 enhances the beiging process and mitochondrial function via lipolysis in adipocytes similarly to the brain-penetrating CB1R antagonist RIM. Our data provide a potential mechanism by which physiologic responses and improvement of energy expenditure, lipid profiles, and insulin sensitivity are improved following dosing with peripheral CB1R antagonists in previous in vivo studies [28,46,47]. We acknowledge our data solely focus on an in vitro model but provide a beginning point to understand the mechanism by which this compound may improve adipose tissue function.…”

Asprosin: A Novel Player in Metabolic Diseases

“…Interestingly, a study by Ma et al investigated the therapeutic effects of AM6545, a peripheral cannabinoid receptor neutral antagonist, on hypometabolic and hypothalamic obesity induced by monosodium glutamate (MSG). They revealed that AM6545 was able to decrease serum asprosin levels, which may accordingly lead to the amelioration of obesity and IR in MSG mice (26). Altogether, asprosin may be a biomarker to indicate adipose tissue mass and a target in the treatment of obesity; however, the observational studies are not able to confirm the cause-and-effect association between asprosin and obesity, and further in vitro and in vivo research needs to be done.…”

Mechanistic Potential and Therapeutic Implications of Cannabinoids in Nonalcoholic Fatty Liver Disease

“…An alternative non-brain-penetrant CB1 antagonist, AM6545, was studied thereafter, demonstrating reduced food intake without malaise, improved glycemic control, improved dyslipidemia, and reversal of hepatic steatosis [ 38 , 39 ]. Proposed mechanisms in the improvement of metabolic factors by AM6545 include an increase in adiponectin and a reduction of TNFα and leptin levels [ 40 ]. JD5037, a peripherally-restricted CB1 inverse agonist, has also been demonstrated to reduce food intake, body weight, and adiposity in animal studies without established psychiatric side effects, showing improved potential for a therapeutic role in hepatic steatosis [ 41 ].…”