Pinch Loss Ameliorates Obesity, Glucose Intolerance and Fatty Liver by Modulating Adipocyte Apoptosis in Mice

The mammalian focal adhesion proteins Pinch1/2 activate integrins and promote cell-ECM adhesion and migration; however, their roles in adipose tissue and metabolism are unclear. Here we find that high fat diet (HFD) feeding dramatically increases expression of Pinch1/2 proteins in white adipose tissues (WAT) in mice. Furthermore, expression of Pinch1 is largely up-regulated in WAT in the Leptin-deficient ob/ob type 2 diabetic mice and obese humans. While mice with the loss of Pinch1 in adipocytes or global Pinch2 do not display any notable phenotypes, deleting Pinch1 in adipocytes and Pinch2 globally significantly decreases body weight and WAT, but not brown adipose tissue (BAT), mass in HFD-, but not normal chow diet (NCD)-, fed mice. Pinch loss ameliorates HFD-induced glucose intolerance and fatty liver. After HFD challenge, Pinch loss slightly, but significantly, accelerates energy expenditure. While Pinch loss decreases adipocyte size and alters adipocyte size distribution, it greatly accelerates cell apoptosis primarily in epididymal WAT and to a less extent subcutaneous WAT. In vitro studies demonstrate that Pinch loss accelerates adipocyte apoptosis by activating the Bim/Caspase-8 pathway. In vivo, genetic ablation of Caspase-8 expression in adipocytes essentially abolishes the ameliorating effects of Pinch deficiency on obesity, glucose intolerance and fatty liver in mice. Thus, we demonstrate a previously unknown function of Pinch in control of adipose mass, glucose and fat metabolism via modulation of adipocyte apoptosis. We may define a novel target for the prevention and treatment of metabolic diseases, such as obesity and diabetics.