title: p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity.
abstract: 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.
authors.affiliation: Gladstone Institute of Neurological Disease, University of California, San Francisco, CA 94158, USA.
authors.forename: Bernat
authors.initials: B
authors.lastname: Baeza-Raja
authors.forename: Pingping
authors.initials: P
authors.lastname: Li
authors.forename: Natacha
authors.initials: N
authors.lastname: Le Moan
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Sachs
authors.forename: Christian
authors.initials: C
authors.lastname: Schachtrup
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Davalos
authors.forename: Eirini
authors.initials: E
authors.lastname: Vagena
authors.forename: Dave
authors.initials: D
authors.lastname: Bridges
authors.forename: Choel
authors.initials: C
authors.lastname: Kim
authors.forename: Alan R
authors.initials: AR
authors.lastname: Saltiel
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Olefsky
authors.forename: Katerina
authors.initials: K
authors.lastname: Akassoglou
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001835:Body Weight; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D057809:HEK293 Cells; D006706:Homeostasis; D006801:Humans; D007333:Insulin Resistance; D051379:Mice; D008969:Molecular Sequence Data; D032342:Muscle Cells / Q000378:metabolism; D018482:Muscle, Skeletal / Q000166:cytology; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D020800:Receptor, Nerve Growth Factor / Q000737:chemistry / Q000172:deficiency / Q000378:metabolism*; D020691:rab GTP-Binding Proteins / Q000378:metabolism; D020696:rab5 GTP-Binding Proteins / Q000378:metabolism
chemical_list: D051275:Glucose Transporter Type 4; D020800:Receptor, Nerve Growth Factor; C495693:Slc2a4 protein, mouse; C544741:Rab22B protein, mouse; D020691:rab GTP-Binding Proteins; D020696:rab5 GTP-Binding Proteins; D005947:Glucose