title: A common haplotype in the G-protein-coupled receptor gene GPR74 is associated with leanness and increased lipolysis.
abstract: 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 beta -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 beta -adrenoceptor signaling to lipolysis in fat cells.
authors.affiliation: Department of Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
authors.forename: Ingrid
authors.initials: I
authors.lastname: Dahlman
authors.forename: Andrea
authors.initials: A
authors.lastname: Dicker
authors.forename: Hong
authors.initials: H
authors.lastname: Jiao
authors.forename: Juha
authors.initials: J
authors.lastname: Kere
authors.forename: Lennart
authors.initials: L
authors.lastname: Blomqvist
authors.forename: Vanessa
authors.initials: V
authors.lastname: van Harmelen
authors.forename: Johan
authors.initials: J
authors.lastname: Hoffstedt
authors.forename: Knut
authors.initials: K
authors.lastname: Borch-Johnsen
authors.forename: Torben
authors.initials: T
authors.lastname: Jorgensen
authors.forename: Torben
authors.initials: T
authors.lastname: Hansen
authors.forename: Oluf
authors.initials: O
authors.lastname: Pedersen
authors.forename: Markku
authors.initials: M
authors.lastname: Laakso
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
mesh_terms: D017667:Adipocytes / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000328:Adult; D000483:Alleles; D003994:Bucladesine / Q000494:pharmacology; D002454:Cell Differentiation; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005787:Gene Frequency; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008066:Lipolysis / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009638:Norepinephrine / Q000494:pharmacology; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D034741:RNA, Small Interfering / Q000494:pharmacology; D018013:Receptors, Neuropeptide / Q000235:genetics*; D013851:Thinness / Q000235:genetics*; D015016:Yohimbine / Q000494:pharmacology
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D034741:RNA, Small Interfering; D018013:Receptors, Neuropeptide; C083929:neuropeptide FF receptor; D015016:Yohimbine; D003994:Bucladesine; D009638:Norepinephrine