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

The ligand-inducible nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ) 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 PPARγ target genes that may contribute to the reduction of circulating free fatty acids after TZD treatment have been identified, the relevant PPARγ 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 PPARγ 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 PPARγ 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 PPARγ-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.

[1]  T. Sakurai,et al.  Aromatic D-amino acids act as chemoattractant factors for human leukocytes through a G protein-coupled receptor, GPR109B , 2009, Proceedings of the National Academy of Sciences.

[2]  F. Kamme,et al.  Lactate Inhibits Lipolysis in Fat Cells through Activation of an Orphan G-protein-coupled Receptor, GPR81* , 2009, Journal of Biological Chemistry.

[3]  S. Kash,et al.  Role of GPR81 in lactate-mediated reduction of adipose lipolysis. , 2008, Biochemical and biophysical research communications.

[4]  Jonathan Schug,et al.  PPARgamma and C/EBP factors orchestrate adipocyte biology via adjacent binding on a genome-wide scale. , 2008, Genes & development.

[5]  H. Stunnenberg,et al.  Genome-wide profiling of PPARgamma:RXR and RNA polymerase II occupancy reveals temporal activation of distinct metabolic pathways and changes in RXR dimer composition during adipogenesis. , 2008, Genes & development.

[6]  Yang Li,et al.  Activation of G protein-coupled receptor 43 in adipocytes leads to inhibition of lipolysis and suppression of plasma free fatty acids. , 2008, Endocrinology.

[7]  J. A. van der Laak,et al.  Peroxisome Proliferator-activated Receptor γ Activation Promotes Infiltration of Alternatively Activated Macrophages into Adipose Tissue* , 2008, Journal of Biological Chemistry.

[8]  W. James.  The epidemiology of obesity: the size of the problem , 2008, Journal of internal medicine.

[9]  J. Reagan,et al.  Elucidation of signaling and functional activities of an orphan GPCR, GPR81 Published, JLR Papers in Press, January 3, 2008. , 2008, Journal of Lipid Research.

[10]  J. Flier,et al.  PPARγ regulates adipose triglyceride lipase in adipocytes in vitro and in vivo , 2007 .

[11]  H. Sul,et al.  Regulation of lipolysis in adipocytes. , 2007, Annual review of nutrition.

[12]  A. Bonvin,et al.  Impaired peroxisome proliferator-activated receptor gamma function through mutation of a conserved salt bridge (R425C) in familial partial lipodystrophy. , 2007, Molecular endocrinology.

[13]  E. Mariman,et al.  Absence of an adipogenic effect of rosiglitazone on mature 3T3-L1 adipocytes: increase of lipid catabolism and reduction of adipokine expression , 2007, Diabetologia.

[14]  T. Kanaya,et al.  Identification of peroxisome-proliferator responsive element in the mouse HSL gene. , 2007, Biochemical and biophysical research communications.

[15]  Bruce M. Spiegelman,et al.  Adipocytes as regulators of energy balance and glucose homeostasis , 2006, Nature.

[16]  H. Stunnenberg,et al.  Peroxisome Proliferator-Activated Receptor Subtype- and Cell-Type-Specific Activation of Genomic Target Genes upon Adenoviral Transgene Delivery , 2006, Molecular and Cellular Biology.

[17]  S. Offermanns.  The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target. , 2006, Trends in pharmacological sciences.

[18]  Michael Lehrke,et al.  The Many Faces of PPARγ , 2005, Cell.

[19]  Ki-Choon Choi,et al.  Acetate and propionate short chain fatty acids stimulate adipogenesis via GPCR43. , 2005, Endocrinology.

[20]  D. Connolly,et al.  (d)-β-Hydroxybutyrate Inhibits Adipocyte Lipolysis via the Nicotinic Acid Receptor PUMA-G* , 2005, Journal of Biological Chemistry.

[21]  Peter Fraser,et al.  Remote control of gene transcription. , 2005, Human molecular genetics.

[22]  A. Sandelin,et al.  Prediction of nuclear hormone receptor response elements. , 2005, Molecular endocrinology.

[23]  V. Large,et al.  Metabolism of lipids in human white adipocyte. , 2004, Diabetes & metabolism.

[24]  J. Auwerx,et al.  Adipose tissue expression of the lipid droplet-associating proteins S3-12 and perilipin is controlled by peroxisome proliferator-activated receptor-gamma. , 2004, Diabetes.

[25]  C. Dani,et al.  Adipocyte differentiation of multipotent cells established from human adipose tissue. , 2004, Biochemical and biophysical research communications.

[26]  R. DeFronzo,et al.  Role of the adipocyte, free fatty acids, and ectopic fat in pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach. , 2004, The Journal of clinical endocrinology and metabolism.

[27]  M. Mozzoli,et al.  Effect of thiazolidinediones on glucose and fatty acid metabolism in patients with type 2 diabetes. , 2003, Metabolism: clinical and experimental.

[28]  H. Matsushime,et al.  Molecular identification of nicotinic acid receptor. , 2003, Biochemical and biophysical research communications.

[29]  S. Dowell,et al.  Molecular Identification of High and Low Affinity Receptors for Nicotinic Acid* , 2003, The Journal of Biological Chemistry.

[30]  W. Harris,et al.  Nocturnal and postprandial free fatty acid kinetics in normal and type 2 diabetic subjects: effects of insulin sensitization therapy. , 2003, Diabetes.

[31]  S. Tunaru,et al.  PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect , 2003, Nature Medicine.

[32]  H. Shimano,et al.  Lipolysis in the absence of hormone-sensitive lipase: evidence for a common mechanism regulating distinct lipases. , 2002, Diabetes.

[33]  M. Kasuga,et al.  Role of peroxisome proliferator-activated receptor-gamma in maintenance of the characteristics of mature 3T3-L1 adipocytes. , 2002, Diabetes.

[34]  J. Holder,et al.  Insulin and rosiglitazone regulation of lipolysis and lipogenesis in human adipose tissue in vitro. , 2002, Diabetes.

[35]  Vincent Lebon,et al.  The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. , 2002, Diabetes.

[36]  J. McGill,et al.  Thiazolidinediones enhance insulin-mediated suppression of fatty acid flux in type 2 diabetes mellitus. , 2002, Metabolism: clinical and experimental.

[37]  K. Pfeffer,et al.  PUMA‐G, an IFN‐γ‐inducible gene in macrophages is a novel member of the seven transmembrane spanning receptor superfamily , 2001, European journal of immunology.

[38]  B. Spiegelman,et al.  PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth* , 2001, The Journal of Biological Chemistry.

[39]  Jilly F. Evans,et al.  Discovery and mapping of ten novel G protein-coupled receptor genes. , 2001, Gene.

[40]  B. Spiegelman,et al.  Degradation of the Peroxisome Proliferator-activated Receptor γ Is Linked to Ligand-dependent Activation* , 2000, The Journal of Biological Chemistry.

[41]  C. Glass,et al.  The coregulator exchange in transcriptional functions of nuclear receptors. , 2000, Genes & development.

[42]  S. O’Rahilly,et al.  Dominant negative mutations in human PPARγ associated with severe insulin resistance, diabetes mellitus and hypertension , 1999, Nature.

[43]  S. Souza,et al.  BRL 49653 blocks the lipolytic actions of tumor necrosis factor-alpha: a potential new insulin-sensitizing mechanism for thiazolidinediones. , 1998, Diabetes.

[44]  J. Lehmann,et al.  Effects of troglitazone and metformin on glucose and lipid metabolism: alterations of two distinct molecular pathways. , 1997, Biochemical pharmacology.

[45]  G. Boden.  Role of Fatty Acids in the Pathogenesis of Insulin Resistance and NIDDM , 1997, Diabetes.

[46]  S. Rössner,et al.  Effects of weight reduction on the regulation of lipolysis in adipocytes of women with upper-body obesity. , 1995, Clinical science.

[47]  J. Lehmann,et al.  An Antidiabetic Thiazolidinedione Is a High Affinity Ligand for Peroxisome Proliferator-activated Receptor γ (PPARγ) (*) , 1995, The Journal of Biological Chemistry.

[48]  M. Jensen,et al.  Influence of body fat distribution on free fatty acid metabolism in obesity. , 1989, The Journal of clinical investigation.

[49]  R. Giorgino,et al.  Influence of Lactate on Isoproterenol-Induced Lipolysis and β-Adrenoceptors Distribution in Human Fat Cells , 1989, Hormone and metabolic research = Hormon- und Stoffwechselforschung = Hormones et metabolisme.

[50]  H. Lebovitz,et al.  Lactate inhibition of lipolysis in exercising man. , 1974, Metabolism: clinical and experimental.

[51]  M. Wabitsch,et al.  Characterization of a human preadipocyte cell strain with high capacity for adipose differentiation , 2001, International Journal of Obesity.

[52]  B. Spiegelman,et al.  Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. , 1993, Science.