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 NH2-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.