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Kilpelainen, TO; Carli, JFM; Skowronski, AA; Sun, Q; Kriebel, J; Feitosa, MF; Hedman, AK; Drong, AW; Hayes, JE; Zhao, JH; Pers, TH; Schick, U.; Grarup, N; Kutalik, Z; Trompet, S; Mangino, M. (Massimo); Kristiansson, K; Beekman, M.; Lyytikainen, LP; J. Eriksson; Henneman, P; Lahti, J; T. Tanaka; Luan, JA; Del Greco, F.; Pasko, D; Renstrom, F; Willems, Sm; Mahajan, A; Rose, LM ... view all 177 authors View less authors (2016)
Publisher: Nature Publishing Group
Languages: English
Types: Article
Subjects: WEIGHT-LOSS, PROVIDES INSIGHTS, /dk/atira/pure/publication/pubmedpublicationtype/D052061, Public Health, Global Health, Social Medicine and Epidemiology, /dk/atira/pure/publication/pubmedpublicationtype/D052060, FAT MASS, GENE-EXPRESSION, 515 Psychology, Folkhälsovetenskap, global hälsa, socialmedicin och epidemiologi, ADIPOSE-TISSUE, Research Support, Non-U.S. Gov't, RECOMBINANT LEPTIN, Medicin och hälsovetenskap, EARLY-ONSET OBESITY, 3111 Biomedicine, Research Support, N.I.H., Intramural, Institut für Medizinische Informationsverarbeitung, Biometrie und Epidemiologie, /dk/atira/pure/publication/pubmedpublicationtype/D013485, Article, Medical and Health Sciences, Medical Genetics, SERUM LEPTIN, INSULIN-RESISTANCE, Research Support, N.I.H., Extramural, Medicinsk genetik, PLASMA LEPTIN, /dk/atira/pure/publication/pubmedpublicationtype/D016428, Journal Article
ddc: ddc:610

Classified by OpenAIRE into

mesheuropmc: hormones, hormone substitutes, and hormone antagonists, digestive, oral, and skin physiology

Leptin is an adipocyte-secreted hormone, the circulating levels of which correlate closely with overall adiposity. Although rare mutations in the leptin (LEP) gene are well known to cause leptin deficiency and severe obesity, no common loci regulating circulating leptin levels have been uncovered. Therefore, we performed a genome-wide association study (GWAS) of circulating leptin levels from 32,161 individuals and followed up loci reaching P<10(-6) in 19,979 additional individuals. We identify five loci robustly associated (P<5 × 10(-8)) with leptin levels in/near LEP, SLC32A1, GCKR, CCNL1 and FTO. Although the association of the FTO obesity locus with leptin levels is abolished by adjustment for BMI, associations of the four other loci are independent of adiposity. The GCKR locus was found associated with multiple metabolic traits in previous GWAS and the CCNL1 locus with birth weight. Knockdown experiments in mouse adipose tissue explants show convincing evidence for adipogenin, a regulator of adipocyte differentiation, as the novel causal gene in the SLC32A1 locus influencing leptin levels. Our findings provide novel insights into the regulation of leptin production by adipose tissue and open new avenues for examining the influence of variation in leptin levels on adiposity and metabolic health.

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