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Liraglutide reduces body weight by upregulation of adenylate cyclase 3.

ABSTRACT: 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.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.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.Based on our research, liraglutide reduces BW, possibly by increasing the expression of AC3.

SUBMITTER: Li Z

PROVIDER: S-EPMC5518799 | biostudies-literature | 2017 May

REPOSITORIES: biostudies-literature

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Liraglutide reduces body weight by upregulation of adenylate cyclase 3.

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

Nutrition & diabetes 20170508 5

<h4>Objective</h4>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.<h4>Methods</h4>A high-fat diet was used to induce obesity in C57BL/6J mice. Both the normal and obese ...[more]

PMID: 28481334

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Project description:The GLP-1 receptor agonist liraglutide is marketed for obesity treatment where it induces body weight reduction possibly via the hypothalamus, which regulates energy homeostasis. In animal studies, acute liraglutide treatment triggers satiety, weight loss and activates thermogenesis in adipose tissue. However, the precise mechanisms how liraglutide affects in particular chronic weight loss are still under investigation.We aimed to evaluate whether chronic hypothalamic or chronic subcutaneous administration of liraglutide induces sustained weight loss through altered adipose tissue function and to what extent hypothalamic neuronal appetite regulators are involved in the liraglutide-induced weight loss in healthy lean rats on a normal diet.We continuously administered liraglutide either intrahypothalamically (10??g per day) or subcutaneously (200??g?kg-1 per day) for 28 days to lean Sprague Dawley rats (n=8 each). We assessed changes in body weight, adipose tissue mass, adipocyte size and adipose tissue volume in the abdominal region by using micro-CT. We analyzed genetic expression patterns of browning, thermogenic and adipocyte differentiation regulators in adipose tissues as well as particular neuronal appetite regulators in the hypothalamus.Intrahypothalamic liraglutide administration induced an 8% body weight reduction at day 9 compared with the control group (P<0.01) and a 7% body weight loss at day 9 compared with subcutaneous liraglutide treatment (P<0.01), supported by a significant reduction in adipose tissue mass and volume with intrahypothalamic liraglutide administration (P<0.05). Our data show that chronic intrahypothalamic liraglutide treatment triggered an 18-fold induction of the hypothalamic mc4r gene (P<0.01) accompanied by a significant increase in circulating thyroxine (T4) levels (P<0.05).Chronic intrahypothalamic liraglutide administration resulted in a profound reduction in body weight and fat mass loss most likely mediated by the hypothalamic melanocortin system rather than by adipose tissue browning or improved thermogenesis.

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Liraglutide reduces body weight by upregulation of adenylate cyclase 3.

Publications

Liraglutide reduces body weight by upregulation of adenylate cyclase 3.

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