Date Published: March 14, 2019
Publisher: Public Library of Science
Author(s): Kira Derkach, Irina Zakharova, Inna Zorina, Andrey Bakhtyukov, Irina Romanova, Liubov Bayunova, Alexander Shpakov, Guillermo López Lluch.
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.
Biguanide metformin (MF) is the first-line pharmacologic agent for management of the type 2 diabetes mellitus and metabolic syndrome . Acting on the peripheral tissues of diabetic individuals, the MF improves their sensitivity to insulin and reduces the plasma glucose levels due to both an inhibition of gluconeogenesis and a decrease of glucose production by hepatocytes . Nowadays, 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 [2–4]. The MF treatment of obese animals and patients has the weight- and fat-lowering effects and improves the glucose and insulin sensitivity [5–8]. 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. There is no evidence of a therapeutic effect of MF on the melanocortin-type obesity that is induced by chronic inhibition of the type 4 melanocortin receptor (MC4R). The weakening of hypothalamic MC4R-signaling can be caused by the reduced level of pro-opiomelanocortin (POMC), a precursor of the melanocortin peptides with MC4R-agonistic activity, by the increased levels of agouti-related peptide (AgRP) and agouti-signaling protein-1 (ASIP1), the endogenous MC4R antagonists, and by the impaired activity of MC4R due to inactivation mutations in the Mc4r gene [9–17]. Currently, the effective drugs to prevent and treat the melanocortin-type obesity are not developed [18–20], which makes it necessary to develop the new pharmacological approaches for its correction, including the use of MF.
The results obtained by us indicate that the agouti-mice with the “yellow” mutation at the mouse agouti locus (Ay) associated with the overexpression of ASIP1, the endogenous antagonist of the MC1R and MC4R had the increased body weight and fat mass, the elevated levels of glucose, insulin and leptin, the impaired glucose tolerance and the altered lipid metabolism (Fig 8). These data indicate the decreased glucose, insulin and leptin sensitivity and the signs of dyslipidemia in MC4R signaling-deficient animals, and are in a good agreement with the previously obtained results on metabolic abnormalities and hyperleptinemia in obese agouti-mice [49, 50, 57].
In agouti-mice with ASIP1-induced melanocortin-type obesity, hypothalamic signaling cascades and factors regulating food intake and metabolic processes and the compensatory mechanisms that are triggered in the response to chronic suppression of the melanocortin system was first studied. It was established that the intrahypothalamic leptin and insulin levels in obese agouti-mice was reduced due to the peripheral leptin and insulin resistance and the impaired transport of leptin and insulin through the BBB. The increase in both the LepR expression and the STAT3 activity was necessary to improve the response of the hypothalamic leptin system to leptin, resulting in the increased expression of the Pomc gene. The increased expression of genes encoding POMC and the melanocortin receptors, MC3R and MC4R, is the compensatory mechanism for prevention of ASIP1-mediated inhibition of the MC4R-signaling in the obese agouti-mice.