Resveratrol ameliorates diabesity-associated insulin resistance and hepatic steatosis via mTORC1 downregulation

Abstract Type 2 diabetes (T2DM) is characterized by insulin resistance and, as a compensatory mechanism, an increase in pancreatic β-cell mass. Obesity, a major risk factor for T2DM diabetes, further exacerbates insulin resistance and contributes to the development of metabolic syndrome. Using an inducible mouse model with a liver-specific deletion of the insulin receptor (iLIRKO), a primary insulin-resistant state appears with concomitant hyperinsulinemia, and an expansion of β cells in an mTORC1-dependent manner. Moreover, an extension of primary insulin resistance to secondary tissues such as white adipose tissue and brown adipose tissue was observed, leading to increased lipolysis, reduced lipid accumulation and smaller adipocyte size-key features of diabesity-related metabolic dysfunction. As a consequence, excess lipids accumulated in the liver, promoting hepatic metabolic disturbances and causing classic complications of metabolic syndrome, such as non-alcoholic fatty liver disease. Since previous data from our lab indicate that the polyphenol resveratrol (Resv) modulates the TSC2 acetylation status and hence regulates mTORC1, we explored its therapeutic potential to counteract the deleterious consequences of insulin resistance in metabolic disorders. Treatment with Resv resulted in reduced insulin resistance and hepatic lipid accumulation. Also, when iLIRKO mice were fed a high-fat diet, insulin resistance and liver lipid accumulation were aggravated, and Resv was able to contribute to the improvement of all these alterations. In summary, Resv emerges as a highly effective treatment capable of ameliorating the progression of insulin resistance, obesity, and associated metabolic disorders such as T2DM.