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 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.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db12-0257/-/DC1.
- Received February 28, 2012.
- Accepted July 26, 2012.
- © 2013 by the American Diabetes Association.
Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.