Rimonabant improves metabolic parameters partially attributed to restoration of high voltage-activated Ca2+ channels in skeletal muscle in HFD-fed mice.

B Chen,N Hu

doi:10.1590/1414-431x20176141

Abstract

Cannabinoid type 1 receptor (CB1R) inhibition tends to be one of the promising strategies for the treatment of obesity and other related metabolic disorders. Although CB1R inhibition may cause adverse psychiatric effects including depression and anxiety, the investigation of the role of peripheral CB1R on weight loss and related metabolic parameters are urgently needed. We first explored the effect of rimonabant, a selective CB1R antagonist/inverse agonist, on some metabolic parameters in high fat-diet (HFD)-induced obesity in mice. Then, real-time PCR and electrophysiology were used to explore the contribution of high voltage-activated Ca2+ channels (HVACCs), especially Cav1.1, on rimonabant's effect in skeletal muscle (SM) in HFD-induced obesity. Five-week HFD feeding caused body weight gain, and decreased glucose/insulin tolerance in mice compared to those in the regular diet group (P<0.05), which was restored by rimonabant treatment compared to the HFD group (P<0.05). Interestingly, HVACCs and Cav1.1 were decreased in soleus muscle cells in the HFD group compared to the control group. Daily treatment with rimonabant for 5 weeks was shown to counter such decrease (P<0.05). Collectively, our findings provided a novel understanding for peripheral CB1R's role in the modulation of body weight and glucose homeostasis and highlight peripheral CB1R as well as Cav1.1 in the SM as potential targets for obesity treatment.

Highlights

Insulin resistance (IR) tends to be an important predictor for various metabolic disorders, including obesity
We found that mice on a 5-week high-fat diet (HFD) had a body weight gain, and decreased glucose tolerance as well as insulin tolerance, which were restored by rimonabant treatment
HFD feeding decreased the expression levels of Cav1.1 and the function of high voltage-activated Ca2+ channels (HVACCs) in Skeletal muscle (SM) cells, which was restored by rimonabant treatment

Summary

Introduction

Insulin resistance (IR) tends to be an important predictor for various metabolic disorders, including obesity. Skeletal muscle (SM) is a principal peripheral tissue in maintaining glucose metabolism and in the development of IR, accounting for the majority of total insulin-stimulated glucose uptake. The importance of Ca2+ signaling in IR and related metabolic disorders has been well established. A rapid elevation in intracellular Ca2+ has been reported to regulate glucose transporter type 4 (GLUT4) traffic and increase surface GLUT4 level [1], which is associated with glucose uptake in muscle and fat cells. Jang and other researchers have demonstrated that decrease of the concentration of free intracellular Ca2+ by a Ca2+ chelator restored glucose infusion rate in SM in a high-fat diet (HFD) rat model [2,3]

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Conclusion