p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity

Insulin resistance is a key factor in the etiology of type 2 diabetes. Insulin-stimulated glucose uptake is mediated by the glucose transporter 4 (GLUT4), which is expressed mainly in skeletal muscle and adipose tissue. Insulin-stimulated translocation of GLUT4 from its intracellular compartment to the plasma membrane is regulated by small guanosine triphosphate hydrolases (GTPases) and is essential for the maintenance of normal glucose homeostasis. Here we show that the p75 neurotrophin receptor (p75 NTR ) is a regulator of glucose uptake and insulin resistance. p75 NTR knockout mice show increased insulin sensitivity on normal chow diet, independent of changes in body weight. Euglycemic-hyperinsulinemic clamp studies demonstrate that deletion of the p75 NTR gene increases the insulin-stimulated glucose disposal rate and suppression of hepatic glucose production. Genetic depletion or shRNA knockdown of p75 NTR in adipocytes or myoblasts increases insulin-stimulated glucose uptake and GLUT4 translocation. Conversely, overexpression of p75 NTR in adipocytes decreases insulin-stimulated glucose transport. In adipocytes, p75 NTR forms a complex with the Rab5 family GTPases Rab5 and Rab31 that regulate GLUT4 trafficking. Rab5 and Rab31 directly interact with p75 NTR primarily via helix 4 of the p75 NTR death domain. Adipocytes from p75 NTR knockout mice show increased Rab5 and decreased Rab31 activities, and dominant negative Rab5 rescues the increase in glucose uptake seen in p75 NTR knockout adipocytes. Our results identify p75 NTR as a unique player in glucose metabolism and suggest that signaling from p75 NTR to Rab5 family GTPases may represent a unique therapeutic target for insulin resistance and diabetes.