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Endothelin-1-stimulated glucose uptake is desensitized by tumor necrosis factor- in 3T3-L1 adipocytes

Department of Nutrition, Case Western Reserve University, Cleveland, Ohio 44106

Submitted 11 April 2003 ; accepted in final form 19 May 2003

Tumor necrosis factor- (TNF-) is a potent inducer of insulin resistance, and increased TNF- expression is associated with impaired glucose disposal. Although insulin is the primary regulator of glucose transport in adipose, endothelin-1, a vasoconstrictor peptide that signals through the heterotrimeric G proteins G_q/11, potently stimulates glucose uptake in 3T3-L1 adipocytes by a mechanism independent of phosphatidylinositol (PI) 3-kinase. Here, we report that exposure of 3T3-L1 adipocytes to TNF- for 48 h dose-dependently decreased endothelin-1-stimulated glucose uptake and translocation of GLUT4 to the plasma membrane. TNF- exposure had no effect on endothelin-1 receptor number at the cell surface. In contrast, TNF- treatment reduced the quantity of G_q/11 and proline-rich tyrosine kinase 2 (PYK2) and decreased endothelin-1-stimulated PYK2-Tyr⁴⁰² tyrosine phosphorylation. Taken together, these results suggest that TNF--induced desensitization of endothelin-1-stimulated GLUT4 translocation and glucose uptake in 3T3-L1 adipocytes is due, at least in part, to a decreased expression of G_q/11, leading to a suppression in tyrosine phosphorylation of PYK2.

adipocytes; glucose homeostasis; G protein-coupled receptors; G_q/11; proline-rich tyrosine kinase 2

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