Alpha4 is Critical for Adipocyte Maintenance and Mitochondrial Homeostasis through Regulation of Insulin Signaling

Insulin signaling is mediated via a network of protein phosphorylation. Dysregulation of this network is central to obesity, type 2 diabetes and metabolic syndrome. Here we have investigated the role of phosphatase binding protein Alpha4 (a4) that is essential for the Ser/Thr protein phosphatase PP2A in insulin action/resistance in adipocytes. Unexpectedly, adipocyte-specific inactivation of a4 impairs insulin-induced Akt-mediated Ser/Thr phosphorylation despite a decrease in the PP2A levels. Interestingly, loss of a4 also reduces insulin-induced insulin receptor Tyr phosphorylation. This occurs through decreased association of a4 with Y-box protein 1 (YBX1), resulting in the enhancement of the Tyr phosphatase PTP1B expression. Moreover, adipocyte-specific knockout of a4 results in impaired adipogenesis and altered mitochondrial oxidation leading to increased inflammation, systemic insulin resistance, hepatosteatosis, islet hyperplasia, and impaired thermogenesis. Thus, the a4 /YBX1-mediated pathway of insulin receptor signaling is essential for maintaining insulin sensitivity, normal adipose tissue homeostasis and systemic metabolism. Overall design: iWAT and BAT mRNA profiles of Control and Ai-a4KO mice.