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.
Highlights
Obesity and closely related cluster of metabolomic diseases such as hyperlipidemia and diabetes, are becoming pandemic chronic disease worldwide, and seriously affect the quality of human life and constitute a heavy burden for the health system of all countries (Cao, 2014)
The weigh-loss effect lasted till the end of the study. 3 mg/kg AM6545 showed no impact on food intake of monosodium glutamate (MSG) mice throughout the test, whereas 10 mg/kg produced a transient reduction in the initial period of administration, it rebounded to the equivalent amount of model control (MC)’s (Figure 1B)
Histopathological analysis of the adipose tissue revealed the size of adipocytes was significantly diminished by AM6545 (p < 0.05 for the comparison of AM6545 vs. MC) (Figure 2)
Summary
Obesity and closely related cluster of metabolomic diseases such as hyperlipidemia and diabetes, are becoming pandemic chronic disease worldwide, and seriously affect the quality of human life and constitute a heavy burden for the health system of all countries (Cao, 2014). Several excellent lead compounds have been described in succession over the past few years, examples are the non-brainpenetrant neutral CB1R antagonist AM6545 and TXX-522, and the peripheral inverse agonists TM38837 and JD-5037 (Cluny et al, 2010; Chorvat et al, 2012; Klumpers et al, 2013; Chen et al, 2017) Their anti-obesity effect and pharmacological mechanism of action are frequently evaluated in diet-induced obesity (DIO) or genetic obese rodent models (Ravinet Trillou et al, 2003; Jourdan et al, 2010; Chen et al, 2017). To some extent, it’s difficult to accurately illuminate the peripheral mechanisms of action of the peripheral CB1R antagonists with these animal models, because it is hard to thoroughly preclude the impact of CNS, especially hypothalamus-associated roles in its effect
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have