Metformin improves hepatic steatosis in diet induced obese FVB/N mice: Alterations of glucose metabolism and hepatic splicing machinery.

Abstract

Metformin can reduce body weight gain and hepatic fat accumulation induced by a high-fat diet (HFD). However, the results obtained in animal models regarding metformin's role in modulating other whole-body and tissue-specific parameters are fragmentary, controversial, and biased, with most studies using the C57BL/6 mouse model. In this study, we examined the effects of metformin on metabolic, endocrine, and hepatic parameters using FVB/N mice, a suitable model for studying diet-induced obesity. We orally administered metformin (250 mg/kg/day) to HFD-induced obese FVB/N mice and analyzed the effects on body weight (BW) gain and composition, glucose/insulin metabolism, liver physiology, growth hormone/insulin-like growth factor 1 (IGF1) axis, and hepatic transcriptional regulation using LFD mice as a control. HFD-fed mice exhibited increased body weight (BW) and total fat mass compared to LFD mice, resulting in increased insulin levels and impaired glucose clearance. Metformin treatment did not alter body weight, food intake, body composition, or fasting glucose under high-fat diet (HFD) or low-fat diet (LFD) conditions. However, only a decrease in insulin was observed in metformin-treated HFD mice. Nevertheless, metformin-treated HFD mice exhibited a lower proportion of hepatic steatosis, inflammation, and necrosis. These changes were accompanied by alterations in the expression profile of genes in the splicing machinery, highlighting possible biomarkers of steatosis development and/or response to metformin. In conclusion, metformin effectively prevents and/or treats liver pathologies in animal models; however, its effects on other metabolic parameters depend on genetic background and metabolic state.