p75 neurotrophin receptor regulates glucose homeostasis and insulin sensitivity

被引:40
作者
Baeza-Raja, Bernat [1 ]
Li, Pingping [2 ]
Le Moan, Natacha [1 ]
Sachs, Benjamin D. [3 ]
Schachtrup, Christian [1 ]
Davalos, Dimitrios [1 ]
Vagena, Eirini [1 ]
Bridges, Dave [4 ]
Kim, Choel [5 ]
Saltiel, Alan R. [4 ,6 ]
Olefsky, Jerrold M. [2 ]
Akassoglou, Katerina [1 ,7 ]
机构
[1] Univ Calif San Francisco, Gladstone Inst Neurol Dis, San Francisco, CA 94158 USA
[2] Univ Calif San Diego, Dept Med, San Diego, CA 92093 USA
[3] Univ Calif San Diego, Dept Pharmacol, San Diego, CA 92093 USA
[4] Univ Michigan, Inst Life Sci, Ann Arbor, MI 48109 USA
[5] Baylor Coll Med, Dept Pharmacol, Verna & Marrs McLean Dept Biochem & Mol Biol, Houston, TX 77030 USA
[6] Univ Michigan, Dept Internal Med & Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
[7] Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA
基金
美国国家卫生研究院;
关键词
3T3L1; brain-derived neurotrophic factor; Rho; peptide array; obesity; AFFINITY NGF RECEPTOR; SIGNALING PATHWAYS; GLUT4; TRAFFICKING; ACTIVATION; TRANSPORT; P75(NTR); TISSUE; RAB5; PHOSPHODIESTERASE; DISPLACEMENT;
D O I
10.1073/pnas.1103638109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 ormyoblasts 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.
引用
收藏
页码:5838 / 5843
页数:6
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