Metformina, fígado e tecido adiposo marrom: lições do modelo de dieta com frutose em camundongos

Abstract

The continuous consumption of fructose causes adverse metabolic changes and might lead to nonalcoholic fatty liver disease (NAFLD). Here, we aimed to investigate the role of metformin hydrochloride in an animal model fed a fructose rich diet, focusing on the molecular markers of lipogenesis, beta-oxidation, and antioxidant defenses in the liver. Also, the structure and thermogenic markers of the brown adipose tissue (BAT) were studied. Male C57BL/6 mice, three months old were divided into a control group (C, fed a standard diet for rodents) and fructose group (F, fed a fructose rich diet) for ten weeks. Then, each group was divided, half of the animals received metformin hydrochloride (M, 250 mg/kg/day), the other half received vehicle for an additional eight weeks: control (C), control+metformin (CM), fructose (F), and fructose+metformin (FM). In the liver, fructose increased hepatic steatosis, insulin resistance and decreased insulin sensitivity in association with higher gene and protein expressions associated with de novo lipogenesis and increased lipid peroxidation. Also, fructose diminished gene and protein expressions of antioxidant enzymes and mitochondrial biogenesis. Metformin reduced de novo lipogenesis and increased mitochondrial biogenesis, thereby increasing beta-oxidation and reducing lipid peroxidation. Metformin upregulated the expression and activity of antioxidant enzymes, providing a defense against increased reactive oxygen species generation. Therefore, a significant reduction in hepatic triglyceride accumulation, steatosis and lipid peroxidation was observed in the FM group. The fat pads and adiposity did not change significantly in the groups, although the F group showed a reduction of energy intake, and both groups F and FM showed reduction of energy expenditure. Metformin led to a more massive BAT in CM and FM, associated with a higher adipocyte proliferation and differentiation, in part by activating pAMK. Metformin also enhanced thermogenic markers in the BAT through adrenergic stimuli and fibroblast growth factor 21. In the BAT, metformin might improve mitochondrial biogenesis, lipolysis, and fatty acid uptake. These findings allow us to conclude that a fructose rich diet affects the liver and BAT, increasing de novo lipogenesis, reducing the antioxidant defenses, and diminishing mitochondrial biogenesis. Metformin treatment, even in continuing the fructose intake, can reverse, at least partially, the liver injury and prevents NAFLD progression to more severe states. Metformin effects are not linked to body mass changes, but affect BAT thermogenesis, mitochondrial biogenesis, and fatty acid uptake