Liraglutide reduces body weight by upregulation of adenylate cyclase 3

Z Li,S Zhou,Y Lai,N Xia,H Pan,F Jiang,Y Liang,Y He

doi:10.1038/nutd.2017.17

Abstract

Objective:According to recent studies, adenylate cyclase 3 (AC3) is associated with obesity. Liraglutide reduces blood glucose levels and body weight (BW). We performed a 2 × 2 factorial experiment to study the relationships among AC3, liraglutide and obesity and to obtain a more comprehensive understanding of the mechanisms underlying the physiological effects of liraglutide on obesity.Methods:A high-fat diet was used to induce obesity in C57BL/6J mice. Both the normal and obese mice were treated with liraglutide (1 mg kg−1) or saline twice daily for 8 weeks. The hepatic levels of the AC3 and glucagon-like peptide receptor (GLP-1R) mRNAs and proteins were measured by quantitative real-time PCR and western blotting, respectively. The serum AC3 levels were detected using a rat/mouse AC3 enzyme-linked immunosorbent assay kit.Results:The administration of liraglutide significantly decreased the BW in obese mice and normal control mice. The BW of obese mice exhibited a more obvious decrease. Hepatic AC3 mRNA and protein levels and serum AC3 levels were significantly reduced in obese mice compared with those in normal control mice. The administration of liraglutide significantly increased the hepatic expression of the AC3 and GLP-1R mRNAs and proteins and serum AC3 levels. The hepatic expression of the AC3 mRNA and protein and serum AC3 levels were negatively correlated with BW loss in the liraglutide-treated group. Pearson’s correlation coefficients for these comparisons are r=−0.448, P=0.048; r=−0.478, P=0.046; and r=−0.909, P=0.000, respectively.Conclusions:Based on our research, liraglutide reduces BW, possibly by increasing the expression of AC3.

Highlights

Epidemiological studies have estimated that global obesity rates have increased steadily over the past 30 years
Effects of liraglutide on the general condition and metabolism of the mice We examined the body weight (BW), fasting blood glucose (FBG) and homeostasis model assessment of insulin resistance (HOMA-IR) to evaluate the animals’ metabolic responses to liraglutide
The BW and FBG of the O+L group were reduced by an average of 21.8% and 45.9%, respectively, compared with the BW and FBG in the O+S group that were reduced by an average of 5.8% and 20.2%, respectively

Summary

Introduction

Epidemiological studies have estimated that global obesity rates have increased steadily over the past 30 years. The cyclic adenosine monophosphate generated by GLP-1 receptor activation may directly influence the exocytosis of insulincontaining granules, and this process has been estimated to account for up to 70% of the entire secretory response.[11] Adenylate cyclase 3 (AC3) is a member of the AC family, and an obesity locus at or near the AC3 gene has been identified in genome-wide association studies.[12,13,14,15] Additional genetic evidence supports an association between AC3 variants and obesity in both Swedish and Han Chinese populations.[16,17] Animal models have highlighted the importance of AC3 signalling in energy homeostasis, as AC3 − / − mice exhibit more fat mass under basal conditions and display a greater susceptibility to obesity induced by consumption of a high-fat diet (HFD).[18] According to our previous studies, hepatic AC3 expression is upregulated by liraglutide in obese and diabetic mice.[19]

Methods

Results

Conclusion