The role of adipocyte apoptosis in development of insulin resistance and non-alcoholic fatty liver disease (NAFLD)

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Obesity, type 2 diabetes, and non-alcoholic fatty liver disease (NAFLD) are closely associated and have reached epidemic proportions worldwide. It has been proposed that low grade inflammation in fat (adipose) tissue may contribute to the development of insulin resistance. However, mechanisms linking adipose tissue inflammation, insulin resistance, and NAFLD remain poorly understood. White and brown adipocytes exhibited different metabolic activity upon hypoxic treatment in our own studies. The guest laboratory is focusing on the mechanisms linking obesity, adipose inflammation, NAFLD, and insulin resistance. They found a pro-apoptotic phenotype in adipose tissue of obese mice and humans. Both accumulation of fat in fat cells and oxidative stress (excessive production of reactive oxygen species) specifically from mitochondria led to apoptosis in adipocytes. Inactivation of the proapoptotic molecule Bid in adipocytes is associated with decreased inflammation in adipose tissue as well as insulin resistance. Therefore the presented proposal will address the influence and mechanisms of adipocyte apoptosis in the development and progression of fatty liver disease. Beside in vitro studies to achieve technical skills mainly in vivo studies in mice with whole-body and tissue-specific knockout of Bid are planned.The results of this proposal may not only shed new insights into the mechanisms linking obesity, type 2 diabetes, NAFLD, and other human diseases but also could translate into new therapeutic strategies to treat these conditions.