A Common Haplotype in the G-Protein–Coupled Receptor Gene GPR74 Is Associated with Leanness and Increased Lipolysis

• Published in: American journal of human genetics 2007-06, Vol.80 (6), p.1115-1124
• Main Authors: Dahlman, Ingrid, Dicker, Andrea, Jiao, Hong, Kere, Juha, Blomqvist, Lennart, van Harmelen, Vanessa, Hoffstedt, Johan, Borch-Johnsen, Knut, Jörgensen, Torben, Hansen, Torben, Pedersen, Oluf, Laakso, Markku, Arner, Peter
• Format: Article
• Language: English
• Subjects: Adipocytes - cytology; Adipocytes - drug effects; Adipocytes - physiology; Adrenergic alpha-Agonists - pharmacology; Adrenergic alpha-Antagonists - pharmacology; Adult; Alleles; Biological and medical sciences; Body fat; Bucladesine - pharmacology; Cell Differentiation; Cells; Cohort Studies; Dose-Response Relationship, Drug; Drug Interactions; Female; Fundamental and applied biological sciences. Psychology; Gene Frequency; General aspects. Genetic counseling; Genes; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genotype & phenotype; Haplotypes; Humans; Linkage Disequilibrium; Lipolysis - genetics; Male; Medical genetics; Medical sciences; Medicin och hälsovetenskap; Middle Aged; Molecular and cellular biology; Norepinephrine - pharmacology; Odds Ratio; Polymorphism, Single Nucleotide; Proteins; Receptors, Neuropeptide - genetics; RNA, Small Interfering - pharmacology; Thinness - genetics; Yohimbine - pharmacology
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1086/518445

The G-protein–coupled receptor GPR74 is a novel candidate gene for body weight regulation. In humans, it is predominantly expressed in brain, heart, and adipose tissue. We report a haplotype in the GPR74 gene, ATAG, with allele frequency ∼4% in Scandinavian cohorts, which was associated with protection against obesity in two samples selected for obese and lean phenotypes (odds ratio for obesity 0.48 and 0.62; nominal P=.0014 and .014; n=1,013 and 1,423, respectively). In a population-based sample, it was associated with lower waist ( P=.02) among 3,937 men and with obesity protection (odds ratio 0.36; P=.036) among those selected for obese or lean phenotypes. The ATAG haplotype was associated with increased adipocyte lipid mobilization (lipolysis) in vivo and in vitro. In human fat cells, GPR74 receptor stimulation and inhibition caused a significant and marked decrease and increase, respectively, of lipolysis, which could be linked to catecholamine stimulation of adipocytes through β-adrenergic receptors. These findings suggest that a common haplotype in the GPR74 gene protects against obesity, which, at least in part, is caused by a relief of inhibition of lipid mobilization from adipose tissue. The latter involves a cross-talk between GPR74 and β-adrenoceptor signaling to lipolysis in fat cells.