Resistin knockout mice exhibit impaired adipocyte glucose-dependent insulinotropic polypeptide receptor (GIPR) expression.
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.
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TNF receptor 2 TNFR2 stress-activated protein kinase SAPK Jun NH(2)-terminal kinase JNK SAPK JNK c-Jun Retn Glucose 12-O-tetradecanoylphorbol-13-acetate (TPA)-response element TRE-III c-Jun Gipr resistin GIP Retn Retn GIPR c-Jun NH(2) Gipr GIP lipoprotein lipase LPL protein kinase B PKB liver kinase B1 LKB1 AMP-activated protein kinase AMPK 12-O-tetradecanoylphorbol-13-acetate resistin GIP GIP Retn Retn incretin hormone Retn GIP PKB LKB1 TPA AMPK LPL Retn GIP GIP Retn Retn GIP receptor GIPR Retn AMP Retn resistin GIP tumor necrosis factor Resistin GIPR glucose-dependent insulinotropic polypeptide receptor fatty acid glucose Glucose-dependent insulinotropic polypeptide TNF