Metformin treatment of rats with diet-induced overweight and hypertriglyceridemia decreases plasma triglyceride concentrations, while decreasing triglyceride and increasing ketone body output by the isolated perfused liver

Metformin has been proposed as a potential drug treatment to reduce liver steatosis. Therefore, the study of the effects of in vivo metformin administration, on hepatic fat metabolism in the isolated perfused liver is of great interest. We have studied the effects of in vivo metformin treatment of rats with experimentally induced overweight, hyperglycemia and hypertriglyceridemia, on plasma hormone and metabolite concentrations, as well as on triglyceride and ketone body output by the isolated perfused livers. Sprague-Dawley rats were fed ad libitum with a high lipid diet for 10 weeks. Then, one rat group was treated for 7 days with 350 microg/kg of BW of metformin per day, whereas the control group received only water. Thereafter, the livers were excised and perfused in vitro under controlled conditions. The hypertriglyceridemic rats had a greater body weight, as well as greater plasma glucose, insulin and triglyceride concentrations, than the control rats fed ordinary chow. In vivo metformin treatment decreased plasma glucose, insulin and triglyceride concentrations. With respect to the overweight, hyperglycemic, hypertriglyceridemic, untreated control rats, the cumulative (i.e. over 3 h of perfusion) triglyceride output by the perfused livers was decreased by >60%, whereas total ketone body (i.e. the sum of 3-hydroxybutyrate and acetoacetate) output was increased by >100% (p < 0.01 for both). In conclusion, the in vivo treatment with metformin of rats with diet-induced overweight and hypertriglyceridemia is capable to re-address hepatic fatty acid metabolism from lipogenesis toward fat oxidation and ketone body production, either directly or through a reduction of insulin concentrations