Publisher: Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachussetts 02115, USA; Department of Clinical Sciences, Genetic and Molecular Epidemiology Unit, Lund University, Malmö 20502, Sweden
Subjects: WEIGHT-LOSS, EARLY-ONSET OBESITY, SERUM LEPTIN, INSULIN-RESISTANCE, PROVIDES INSIGHTS, 3111 Biomedicine, PLASMA LEPTIN, FAT MASS, GENE-EXPRESSION, 515 Psychology, ADIPOSE-TISSUE, RECOMBINANT LEPTIN
This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/ncomms10494
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 Po10 6 in 19,979 additional individuals. We identify five loci robustly associated (Po5 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.
Funding for this study was provided by the Academy of Finland (41071, 117787, 118065, 121584, 124282, 126925, 129494, 129322, 129378, 130326, 134309, 134791, 136895, 139635, 250207, 263836, 286284 and 263924); Ahokas Foundation; ALF/LUA research grant in Gothenburg; Amgen; Augustinus Foundation; Becket Foundation; Bristol-Myers Squibb; British Heart Foundation programme (PG/13/66/30442 and PG/07/131/24254); Canadian Institutes of Health Research (FRCN-CCT-83028); Centre for Medical Systems Biology; Danish Centre for Health Technology Assessment; Danish Council for Independent Research (DFF-1333-00124 and DFF-1331-00730B); Danish Diabetes Association; Danish Heart Foundation; Danish Pharmaceutical Association; Danish Research Council; Department of Health Policy Research Programme (0090049); Diabetes UK; Donald W. Reynolds Foundation; Dutch Arthritis Association (DAA 2010_017); Dutch government (NWO 184.021.007); Emil Aaltonen Foundation; Erasmus MC; Erasmus University; European Commission (FP6-LSHG-CT-2006-018947, FP6-LSHG-CT-2006-01947, HEALTH-F2-2008-201865-GEFOS, FP7-201668, FP7-223004, FP7-259679, FP7-305739 and FP7-IDEAS-ERC-323195); European Regional Development Fund; EUROSPAN; Faculty of Biology and Medicine of Lausanne; Finnish Centre for Pensions; Finnish Cultural Foundation; Finnish Diabetes Research Society; Finnish Foundation of Cardiovascular Research; Finnish Foundation for Pediatric Research; Finnish National Institute for Health and Welfare; Finnish Special Governmental Subsidy for Health Sciences; Finska Läkaresällskapet; Folkhälsan Research Foundation; Genetic Laboratory of the Department of Internal Medicine, Erasmus MC; German Center for Diabetes Research (DZD); German Federal Ministry of Education and Research; GlaxoSmithKline; Göran Gustafsson Foundation; Heart Foundation of Northern Sweden; Helmholtz Zentrum München; Ib Henriksen Foundation; Innovation-Oriented Research Program on Genomics (SenterNovem IGE05007); Italian Ministry of Health (ICS110.1/RF97.71); John W. Barton Sr. Chair in Genetics and Nutrition; Juho Vainio Foundation; King’s College London; Knut and Alice Wallenberg Foundation; Kuopio, Tampere and Turku University Hospital Medical Funds (X51001, 9M048, 9N035); Leiden University Medical Centre; Li Ka Shing Foundation; Liv och Hälsa; Local Government Pensions Institution; Ludwig-Maximilians-Universität; Lundbeck Foundation; Lundberg Foundation; Medical Research Council (MC_U106179471, MC_UU_12013/3, and MC_UU_12013/8); Medical Research Council-GlaxoSmithKline pilot programme grant (G0701863); Ministry of Education, Culture and Science of the Netherlands; Ministry of health, Welfare and Sports of the Netherlands; Ministry of Health and Department of Educational Assistance, University and Research of the Autonomous Province of Bolzano; Danish Ministry of Internal Affairs and Health; Munich Center of Health Sciences; Municipality of Rotterdam; National Cancer Institute (CA047988); National Eye Institute; National Institute on Aging (Intramural research programme, N01AG62101, N01AG62103, N01AG62106, 1R01AG032098-01A1, 263MD9164 and 263 MD 821336); National Institute for Health Research; National Institutes of Health (DK52431, HG004399, HG004446, CA087969, CA055075, DK058845, CA65725, CA49449, CA67262, CA50385 and UO1CA098233); Netherlands Brain Foundation (HersenStichting Nederland); Netherlands Consortium for Healthy Aging (050-060-810); Netherlands Genomics Initiative; Netherlands Heart Foundation (2001 D 032); Netherlands Organization for Scientific Research (175-010-2005-011, 904-61-095, 911-03-012, 911-03-016, 917-66-344 and 911-03-012); Netherlands Organization for the Health Research and Development; National Heart, Lung, and Blood Institute (5R01HL068891, 5R01HL087700, R01HL117078, HHSN26800625226C, HHSN268200782096C, HL-043851, HL-045670, HL080467, N01-HC95159, N01-HC-95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, N01-HC-95169, N02-HL-64278, N01-HC-65226, R01-HL-071051, R01-HL-071205, R01-HL-071250, R01-HL-071251, R01-HL-071252, R01-HL-071258, R01-HL-071259, R01-HL-088451, R00-HL-098459, U01-HG007033, UL1-RR-24156, UL1-RR-25005, UL1-TR-000040 and UL1-TR-001079); National Health Service Foundation Trust; National Institutes of Diabetes and Digestive and Kidney Diseases (1R01DK080015, R01DK089256, 5R01DK068336, 5R01DK075681 and 5R01DK07568102); Novo Nordisk; Novo Nordisk Foundation; New York Obesity Nutrition Research Center Pilot and Feasilibity Grant (DK-26687); Orion-Farmos Research Foundation; Pfizer Inc.; Paavo Nurmi Foundation; Påhlssons Foundation; Research Foundation of Copenhagen County; Roche Pharmaceuticals; Research Institute for Diseases in the Elderly (014-93-015; RIDE2); Samfundet Folkhälsan; Signe and Ane Gyllenberg Foundation; Sigrid Jusélius Foundation; Social Insurance Institution of Finland; South Tyrolean Sparkasse Foundation; Swedish Diabetes Association; Swedish Diabetes Foundation; Swedish Foundation for Strategic Research; Swedish Heart-Lung Foundation (20140422); Swedish Research Council (2012-1397); Swiss Institute of Bioinformatics; Swiss National Science Foundation (3100AO-116323/1, 33CSCO-122661, 33CS30-139468 and 33CS30-148401); Tampere Tuberculosis Foundation; Torsten and Ragnar Söderberg’s Foundation; Umeå University Career Development Award; Unilever Colworth; Wellcome Trust (WT064890, WT089062, WT090532, WT098017, WT098051, WT091551, 081917/Z/07/Z and 086596/Z/08/Z); Wellcome Trust Centre for Human Genetics core funding (090532); Wissenschaftsoffensive TMO; Yrjö Jahnsson Foundation.
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