[The effect of Metformin on metabolic parameters and hypothalamic signaling systems in rats with obesity induced by a...

Metformin (MF), a first-line drug in the treatment of diabetes mellitus, has been used in the recent years to treat obesity. Its therapeutic effect is due not only to the influence on the peripheral tissues, but also on the hypothalamus, which controls food behavior and energy metabolism. The aim was to study the effect of MF therapy (200 mg/kg/day, 8 weeks) in rats with obesity caused by a high-carbohydrate/high-fat diet on the metabolic and hormonal parameters and functional state of the hypothalamic signaling systems. The MF treatment of obese rats (the group ObM) normalized the food behavior, reduced the body and fat weight and the glucose, insulin and leptin levels, increased the sensitivity to glucose and insulin, improved the lipid metabolism, and restored the Ser473-phosphorylation of Akt-kinase in the liver. In the hypothalamus, the stimulating adenylyl cyclase (AC) effects of the agonists of type 4 melanocortin receptor and type 1 dopamine receptor were partially restored, the inhibitory AC effect of the agonists of subtype 1B serotonin receptor (5-HT1BR) was increased, which was associated with an increase in Htr1b gene expression, and the stimulating effect of the 5-HT6R-agonist EMD-386088 was normalized. At the same time, the differences in the activity of the leptin and insulin systems and the ratio of anorexigenic and orexigenic factors in the hypothalamus of the rat groups Ob and ObM were insignificant. Thus, MF treatment changes functional activity of the hypothalamic melanocortin, dopamine and serotonin systems in obese rats, which is one of the reasons to decrease their food intake and to restore the metabolic indicators and insulin sensitivity.