The action of metformin is modulated by the metabolic context

Identifier:  TFG:103

Handle: https://hdl.handle.net/20.500.11797/TFG103

Authors:  Abengochea Molar, Aran

Abstract:
Introduction: Obesity and its associated morbidities are a health concern no longer restricted to Western societies. Obesity occurs as a consequence of multiple factors and is closely associated with inflammation, insulin resistance and other features of the metabolic syndrome, which are a well-known risk factor for the development of chronic liver diseases, such as non-alcoholic fatty liver disease (NAFLD). Insulin sensitizers, and particularly, metformin, have been proposed as a supportive treatment in these patients. Purpose: The aim of the present study was to determine the potential beneficial effects of this drug in low-density lipoprotein receptor (LDL) knockout mice (LDLr -/-) serving as a mouse model of NAFLD. Methods: Male LDLr -/- mice were fed with either a low- or high-fat diet for 14 weeks and treated with either metformin (200 mg/kg) or placebo. Results: Multiple and significant combinatorial effects between metformin and diet were found. Metformin therapy was associated with reduced body weight, antiinflammatory processes and an amelioration of hepatic steatosis, white adipose tissue phenotype and a great number of metabolic parameters uniquely observed under a low-fat diet. In fact, the effects of metformin under a high-fat diet in this mouse model not only showed no improvement but also a worsening effect in many of the parameters evaluated. Furthermore, the beneficial effect of metformin may be at least partly dependent on AMPK activation and that the AMPK signalling pathway could be an important mediator of these effects. Conclusion: Taken together, these results suggest that the action of the drug, specifically in this mouse model is modulated by the metabolic context in a low-caloric dependent- manner.