title: Endothelin-1-stimulated glucose uptake is desensitized by tumor necrosis factor-alpha in 3T3-L1 adipocytes.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is a potent inducer of insulin resistance, and increased TNF-alpha 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 Galphaq/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-alpha for 48 h dose-dependently decreased endothelin-1-stimulated glucose uptake and translocation of GLUT4 to the plasma membrane. TNF-alpha exposure had no effect on endothelin-1 receptor number at the cell surface. In contrast, TNF-alpha treatment reduced the quantity of Galphaq/11 and proline-rich tyrosine kinase 2 (PYK2) and decreased endothelin-1-stimulated PYK2-Tyr402 tyrosine phosphorylation. Taken together, these results suggest that TNF-alpha-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 Galphaq/11, leading to a suppression in tyrosine phosphorylation of PYK2.
authors.affiliation: Department of Nutrition, Case Western Reserve University, Cleveland, OH 44106, USA.
authors.forename: Nadia
authors.initials: N
authors.lastname: Rachdaoui
authors.forename: Laura E
authors.initials: LE
authors.lastname: Nagy
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004347:Drug Interactions; D019332:Endothelin-1 / Q000494:pharmacology*; D051418:Focal Adhesion Kinase 2; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D005947:Glucose / Q000493:pharmacokinetics*; D051275:Glucose Transporter Type 4; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism; D006706:Homeostasis / Q000187:drug effects; D051379:Mice; D009004:Monosaccharide Transport Proteins / Q000378:metabolism; D009124:Muscle Proteins; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014443:Tyrosine / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D019332:Endothelin-1; D051275:Glucose Transporter Type 4; D009004:Monosaccharide Transport Proteins; D009124:Muscle Proteins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C495693:Slc2a4 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D051418:Focal Adhesion Kinase 2; C496053:Ptk2b protein, mouse; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D005947:Glucose