Endocrine Abstracts

Objectives: Previous studies have shown that metformin can reduce high-fat diet (HFD)-induced body weight gain and fat accumulation in the liver. However, the results obtained in animal models regarding the implication of metformin in the modulation of other whole-body and tissue-specific parameters, are controversial or need to be further explored. Consequently, we aimed to explore the capacity of metformin in modulating glucose/insulin metabolism, liver function, adiposity, circulating hormones and lipids, food intake and energy expenditure in HFD-induced obese mice using a different inbred strain, FVB/N, which has been demonstrated to be a suitable and complementary model for diet-induced obesity (DIO) studies.

Materials and methods: Orally administered metformin (250 mg/kg/day) was used in HFD-induced obese FVB/N mice. The effects of metformin on body weight gain and composition, glucose/insulin metabolism, liver physiology, growth hormone and IGF1 axis and hepatic transcriptional regulation were analyzed using animals fed a low-fat diet (LFD) as control.

Results: HFD-fed mice exhibited significantly increased body weight compared to LFD mice, which was accompanied by the proportional increase in total fat mass as assessed by NMR. The observed increase in body weight was due to higher caloric intake. HFD consumption led to an increase in insulin and a non-significant increase in glucose. HFD-fed mice also exhibited impaired glucose tolerance, although no alterations in insulin tolerance were observed. Metformin treatment induced unexpected metabolic effects in HFD-fed mice, with no significant impact on LFD-fed mice. Specifically, metformin treatment did not induce changes in body weight, food intake, body composition, or fasting glucose under HFD or LFD conditions, whereas only a decrease in insulin was observed in metformin-treated HFD mice. However, a substantial effect was observed at the hepatic level as metformin-treated HFD mice exhibited a significantly lower proportion of hepatic steatosis, inflammation and necrosis, while LFD mice exhibited a more inconsistent role. These changes were accompanied by changes in the expression of genes involved in the control of gene expression, suggesting possible biomarkers in the development of steatosis and/or response to metformin.

Conclusion: In animal models, metformin exerts a potent role in the prevention and/or development of liver pathologies, although its effect on other metabolic parameters is highly dependent on the genetic background of the animals and their metabolic state.