Effect of Metformin on Metabolic Parameters and Hypothalamic Signaling Systems in Rats with Obesity Induced by a High-Carbohydrate and High-Fat Diet

Metformin (MF), a first-line drug in the treatment of diabetes mellitus, has been used in 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 goal was to study the effect of MF therapy (200 mg/kg/day, 8 weeks) in rats with obesity caused by a high-carbohydrate and high-fat diet on metabolic and hormonal parameters and the functional state of the hypothalamic signaling systems. MF treatment of obese rats (the group ObM) normalized food behavior; reduced the body weight and fat weight and the glucose, insulin, and leptin levels; increased sensitivity to glucose and insulin; improved the lipid metabolism; and restored Ser⁴⁷³ phosphorylation of Akt kinase in the liver. In the hypothalamus, the stimulating effects of agonists of type-4 melanocortin receptor and type-1 dopamine receptor on adenylyl cyclase (AC) were partially restored, the inhibitory effect on AC of agonists of subtype-1B serotonin receptor (5-HT_1BR) increased (which was associated with an increase in Htr1b gene expression), and the stimulating effect of the 5-HT₆R agonist EMD-386088 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 the functional activity of the hypothalamic melanocortin, dopamine, and serotonin systems in obese rats, which is one way to decrease their food intake and to restore the metabolic parameters and insulin sensitivity.