A common haplotype in the G-protein-coupled receptor gene GPR74 is associated with leanness and increased lipolysis.
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.
Dahlman
Ingrid
I
Department of Medicine, Karolinska University Hospital, Huddinge, Stockholm, Sweden.
Dicker
Andrea
A
Jiao
Hong
H
Kere
Juha
J
Blomqvist
Lennart
L
van Harmelen
Vanessa
V
Hoffstedt
Johan
J
Borch-Johnsen
Knut
K
Jorgensen
Torben
T
Hansen
Torben
T
Pedersen
Oluf
O
Laakso
Markku
M
Arner
Peter
P
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
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