The evidence of metabolic-improving effect of metformin in Ay/a mice with genetically-induced melanocortin obesity and the contribution of hypothalamic mechanisms to this effect

Kira Derkach,Inna Zorina,Liubov Bayunova,Irina Zakharova,Alexander Shpakov,Andrey Bakhtyukov,Irina Romanova,Guillermo López Lluch

doi:10.1371/journal.pone.0213779

Abstract

In diet-induced obesity, metformin (MF) has weight-lowering effect and improves glucose homeostasis and insulin sensitivity. However, there is no information on the efficiency of MF and the mechanisms of its action in melanocortin-type obesity. We studied the effect of the 10-day treatment with MF at the doses of 200, 400 and 600 mg/kg/day on the food intake and the metabolic and hormonal parameters in female C57Bl/6J (genotype Ay/a) agouti-mice with melanocortin-type obesity, and the influence of MF on the hypothalamic signaling in obese animals at the most effective metabolic dose (600 mg/kg/day). MF treatment led to a decrease in food intake, the body and fat weights, the plasma levels of glucose, insulin and leptin, all increased in agouti-mice, to an improvement of the lipid profile and glucose sensitivity, and to a reduced fatty liver degeneration. In the hypothalamus of obese agouti-mice, the leptin and insulin content was reduced and the expression of the genes encoding leptin receptor (LepR), MC3- and MC4-melanocortin receptors and pro-opiomelanocortin (POMC), the precursor of anorexigenic melanocortin peptides, was increased. The activities of AMP-activated kinase (AMPK) and the transcriptional factor STAT3 were increased, while Akt-kinase activity did not change from control C57Bl/6J (a/a) mice. In the hypothalamus of MF-treated agouti-mice (10 days, 600 mg/kg/day), the leptin and insulin content was restored, Akt-kinase activity was increased, and the activities of AMPK and STAT3 were reduced and did not differ from control mice. In the hypothalamus of MF-treated agouti-mice, the Pomc gene expression was six times higher than in control, while the gene expression for orexigenic neuropeptide Y was decreased by 39%. Thus, we first showed that MF treatment leads to an improvement of metabolic parameters and a decrease of hyperleptinemia and hyperinsulinaemia in genetically-induced melanocortin obesity, and the specific changes in the hypothalamic signaling makes a significant contribution to this effect of MF.

Highlights

Biguanide metformin (MF) is the first-line pharmacologic agent for management of the type 2 diabetes mellitus and metabolic syndrome [1]
In agouti-mice treated by MF, including a daily dose 600 mg/kg/ day, no mortality, indigestion, diarrhea and visible signs of pathological processes were observed. This data shows that MF is effective in reducing the body and fat weight and the food intake and is able to improve the lipid metabolism in genetically-induced melanocortin obesity
We showed a significant increase in the Lepr, Pomc, Mc3r and Mc4r genes expression in obese agouti-mice as compared to control (Fig 7 and S2 Dataset)

Summary

Introduction

Biguanide metformin (MF) is the first-line pharmacologic agent for management of the type 2 diabetes mellitus and metabolic syndrome [1]. The obtained clinical evidences show that the MF can be an effective drug for the treatment of both diabetic and non-diabetic patients with obesity [2,3,4]. The MF treatment of obese animals and patients has the weight- and fat-lowering effects and improves the glucose and insulin sensitivity [5,6,7,8]. The effectiveness of MF to treat the different types of obesity varies greatly and depends on the etiology of obesity, its severity and duration, as well as on the comorbid metabolic disorders, such as diabetes mellitus and metabolic syndrome. The effective drugs to prevent and treat the melanocortin-type obesity are not developed [18,19,20], which makes it necessary to develop the new pharmacological approaches for its correction, including the use of MF

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Discussion

Conclusion