title: Resistin knockout mice exhibit impaired adipocyte glucose-dependent insulinotropic polypeptide receptor (GIPR) expression.
abstract: Glucose-dependent insulinotropic polypeptide (GIP) is an incretin hormone that also plays a regulatory role in fat metabolism. In 3T3-L1 cells, resistin was demonstrated to be a key mediator of GIP stimulation of lipoprotein lipase (LPL) activity, involving activation of protein kinase B (PKB) and reduced phosphorylation of liver kinase B1 (LKB1) and AMP-activated protein kinase (AMPK). The current study was initiated to determine whether resistin has additional roles in GIP-regulated adipocyte functions. Analysis of primary adipocytes isolated from Retn(-/-), Retn(+/-), and Retn(+/+) mice found that GIP stimulated the PKB/LKB1/AMPK/LPL pathway and fatty acid uptake only in Retn(+/+) adipocytes, suggesting that GIP signaling and/or GIP responsiveness were compromised in Retn(+/-) and Retn(-/-) adipocytes. GIP receptor (GIPR) protein and mRNA were decreased in Retn(+/-) and Retn(-/-) adipocytes, but resistin treatment rescued LPL responsiveness to GIP. In addition, genes encoding tumor necrosis factor (TNF), TNF receptor 2 (TNFR2), and the signaling proteins stress-activated protein kinase (SAPK)/Jun NH(2)-terminal kinase (JNK), were downregulated, and phosphorylated levels of SAPK/JNK/c-Jun were decreased in Retn(-/-) mice. Chromatin immunoprecipitation assays were used to identify a 12-O-tetradecanoylphorbol-13-acetate (TPA)-response element (TRE-III) responsible for c-Jun-mediated transcriptional activation of Gipr. Blunted GIP responsiveness in Retn(+/-) and Retn(-/-) adipocytes was therefore largely due to the greatly reduced GIPR expression associated with decreased c-Jun-mediated transcriptional activation of Gipr.
authors.affiliation: Department of Cellular & Physiological Sciences and the Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Su-Jin
authors.initials: SJ
authors.lastname: Kim
authors.forename: Cuilan
authors.initials: C
authors.lastname: Nian
authors.forename: Christopher H S
authors.initials: CH
authors.lastname: McIntosh
mesh_terms: D041721:3T3-L1 Cells; D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism*; D000818:Animals; D002273:Carcinogens / Q000494:pharmacology; D002478:Cells, Cultured; D005227:Fatty Acids / Q000378:metabolism; D005749:Gastric Inhibitory Polypeptide / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D008071:Lipoprotein Lipase / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D011964:Receptors, Gastrointestinal Hormone / Q000096:biosynthesis*; D047889:Receptors, Tumor Necrosis Factor, Type II / Q000096:biosynthesis / Q000235:genetics; D052243:Resistin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D002273:Carcinogens; D005227:Fatty Acids; D011725:Pyridines; D011964:Receptors, Gastrointestinal Hormone; D047889:Receptors, Tumor Necrosis Factor, Type II; D052243:Resistin; C499623:Retn protein, mouse; C431843:tris(2-pyridylmethyl)amine; D005749:Gastric Inhibitory Polypeptide; C041086:gastric inhibitory polypeptide receptor; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; C491654:Stk11 protein, mouse; D048055:Mitogen-Activated Protein Kinase 8; D055372:AMP-Activated Protein Kinases; D008071:Lipoprotein Lipase