Effect of High-Dose Metformin on the Metabolic Parameters and Functional State of the Liver of Agouti Mice with Melanocortin Obesity

The effectiveness of high-dose metformin (MF) for the treatment of endocrine and oncological diseases has been shown in recent years. However, the use of high-dose MF may be associated with lactic acidosis and liver dysfunctions. The goal of the work was to study the effect of long-term (10-day) oral administration of a relatively high dose of MF (600 mg/kg per day) to yellow C57Bl/6J (A^y/a) Agouti line mice with melanocortin-type obesity on liver function, which was evaluated based on the hepatocyte morphology and steatosis severity, the expression of inflammatory and apoptotic factors, and the aminotransferase activity, as well as on the plasma lactate level in the animals. In Agouti mice, MF (600 mg/kg per day) caused a decrease in body and fat mass, led to reduced hyperglycemia, hyperinsulinemia, and hyperleptinemia, and restored sensitivity to glucose and insulin. At the same time, small- and large-drop fatty and hydropic degeneration were attenuated in the liver of Agouti line mice treated with MF. The expression of proinflammatory IL-1β and proapoptotic Bax protein and the Bax/Bcl-2 ratio did not differ from the control C57Bl/6J (a/a) mice. The activity of alanine aminotransferase was normalized in the blood of Agouti mice treated with MF, and the lactate level increased, but to a moderate degree. It was concluded that high-dose MF did not induce lactic acidosis in Agouti mice. At the same time, it restored the liver functions impaired by melanocortin obesity. This allows the use of the high-dose MF to be considered a possible means to treat obesity and metabolic disorders associated with hepatic steatosis.