Peroxisome Proliferator-activated Receptor gamma Regulates Expression of the Anti-lipolytic G-protein-coupled Receptor 81 (GPR81/Gpr81)

E.H. Jeninga, A. Bugge, R. Nielsen, A.H. Kersten, N. Hamers, C. Dani, M. Wabitsch, R. Berger, H.G. Stunnenberg, S. Mandrup, E. Kalkhoven

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Abstract

The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR gamma) plays a key role in the differentiation, maintenance, and function of adipocytes and is the molecular target for the insulin-sensitizing thiazoledinediones (TZDs). Although a number of PPAR gamma target genes that may contribute to the reduction of circulating free fatty acids after TZD treatment have been identified, the relevant PPAR gamma target genes that may exert the anti-lipolytic effect of TZDs are unknown. Here we identified the anti-lipolytic human G-protein-coupled receptor 81 (GPR81), GPR109A, and the (human-specific) GPR109B genes as well as the mouse Gpr81 and Gpr109A genes as novel TZD-induced genes in mature adipocytes. GPR81/Gpr81 is a direct PPAR gamma target gene, because mRNA expression of GPR81/Gpr81 (and GPR109A/Gpr109A) increased in mature human and murine adipocytes as well as in vivo in epididymal fat pads of mice upon rosiglitazone stimulation, whereas small interfering RNA-mediated knockdown of PPAR gamma in differentiated 3T3-L1 adipocytes showed a significant decrease in Gpr81 protein expression. In addition, chromatin immunoprecipitation sequencing analysis in differentiated 3T3-L1 cells revealed a conserved PPAR: retinoid X receptor-binding site in the proximal promoter of the Gpr81 gene, which was proven to be functional by electromobility shift assay and reporter assays. Importantly, small interfering RNA-mediated knockdown of Gpr81 partly reversed the inhibitory effect of TZDs on lipolysis in 3T3-L1 adipocytes. The coordinated PPAR gamma-mediated regulation of the GPR81/Gpr81 and GPR109A/Gpr109A genes (and GPR109B in humans) presents a novel mechanism by which TZDs may reduce circulating free fatty acid levels and perhaps ameliorate insulin resistance in obese patients.
Original languageEnglish
Pages (from-to)26385-26393
JournalJournal of Biological Chemistry
Volume284
Issue number39
DOIs
Publication statusPublished - 2009

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Keywords

  • nicotinic-acid receptor
  • type-2 diabetes-mellitus
  • mature 3t3-l1 adipocytes
  • necrosis-factor-alpha
  • human adipose-tissue
  • free fatty-acids
  • ppar-gamma
  • puma-g
  • insulin-resistance
  • molecular-identification

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