The role of the PNPLA3 I148M polymorphism for adipose tissue function in health and disease

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Obesity is a major risk factor for metabolic syndrome and its complications, such as diabetes, cardiovascular disease and nonalcoholic steatohepatitis (NASH). Hyperalimentation but also genetic factors contribute to disease onset and progression. This makes the metabolic syndrome a systemic disease with multiple organs affected. The adipose tissue (AT) with its three major compartments, subcutaneous-, visceral- and brown AT is a key player in metabolic syndrome and has been increasingly recognized in the past years. It has a role in energy -storage and –expenditure, Insulin sensitivity and as an endocrine organ, mediating multiple physiological processes through the secretion of factors termed adipokines.Recently, a polymorphism of the phospholipase PNPLA3 has been identified as a genetic risk factor, present in approximately 20% of the Caucasian population. A reduced lipase- activity of PNPLA3 leads to the onset and progression of NASH and aggravation of other liver diseases such as alcoholic liver disease and viral hepatitis. The role of PNPLA3 in other organs is currently unclear. Interestingly, individuals bearing the polymorphism show an altered body composition with a favorable AT distribution. However, other reports have revealed an increased risk for the development of metabolic syndrome in the presence of obesity. So far, the role of PNPLA3 in metabolic syndrome remains elusive.Recently, a mouse model has been established, resembling the PNPLA3 polymorphism in mice and leading to NASH. As additional control, the model comprises a mouse strain with a lipase-dead mutant. Though, we have an excellent model to study the function and physiology of this important human risk factor.In this project, we aim to investigate the role of PNPLA3 in AT for the development of NASH and metabolic syndrome. First, we will examine the regulation of PNPLA3 and its impact on major AT functions, in lean and obese animals. This comprises the glucose- and lipid- metabolism, indirect calorimetry and body composition analysis. On cellular level, we will characterize the lipid metabolism and brown AT function, in particular thermogenesis. In a next step, we plan to identify factors that can serve as adipokines and potentially mediate effects outside the AT, such as in liver. Finally, we will evaluate our data in tissue and serum of a human cohort of obese patients with known PNPLA3 status.In summary, this project will help to understand the role of PNPLA3 in AT and its impact on metabolic disease and liver disease. This will help to develop new therapeutic strategies for patients with metabolic syndrome and to identify patients at risk for disease onset and progression.