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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

ABSTRACT: Leptin influences food intake by informing the brain about the status of body fat stores. Rare LEP mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin concentrations. We identify five novel variants, including four missense variants, in LEP, ZNF800, KLHL31, and ACTL9, and one intergenic variant near KLF14. The missense variant Val94Met (rs17151919) in LEP was common in individuals of African ancestry only, and its association with lower leptin concentrations was specific to this ancestry (P = 2 × 10^-16, n = 3,901). Using in vitro analyses, we show that the Met94 allele decreases leptin secretion. We also show that the Met94 allele is associated with higher BMI in young African-ancestry children but not in adults, suggesting that leptin regulates early adiposity.

SUBMITTER: Yaghootkar H

PROVIDER: S-EPMC7679778 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Yaghootkar Hanieh H Zhang Yiying Y Spracklen Cassandra N CN Karaderi Tugce T Huang Lam Opal LO Bradfield Jonathan J Schurmann Claudia C Fine Rebecca S RS Preuss Michael H MH Kutalik Zoltan Z Wittemans Laura B L LBL Lu Yingchang Y Metz Sophia S Willems Sara M SM Li-Gao Ruifang R Grarup Niels N Wang Shuai S Molnos Sophie S Sandoval-Zárate América A AA Nalls Mike A MA Lange Leslie A LA Haesser Jeffrey J Guo Xiuqing X Lyytikäinen Leo-Pekka LP Feitosa Mary F MF Sitlani Colleen M CM Venturini Cristina C Mahajan Anubha A Kacprowski Tim T Wang Carol A CA Chasman Daniel I DI Amin Najaf N Broer Linda L Robertson Neil N Young Kristin L KL Allison Matthew M Auer Paul L PL Blüher Matthias M Borja Judith B JB Bork-Jensen Jette J Carrasquilla Germán D GD Christofidou Paraskevi P Demirkan Ayse A Doege Claudia A CA Garcia Melissa E ME Graff Mariaelisa M Guo Kaiying K Hakonarson Hakon H Hong Jaeyoung J Ida Chen Yii-Der YD Jackson Rebecca R Jakupović Hermina H Jousilahti Pekka P Justice Anne E AE Kähönen Mika M Kizer Jorge R JR Kriebel Jennifer J LeDuc Charles A CA Li Jin J Lind Lars L Luan Jian'an J Mackey David A DA Mangino Massimo M Männistö Satu S Martin Carli Jayne F JF Medina-Gomez Carolina C Mook-Kanamori Dennis O DO Morris Andrew P AP de Mutsert Renée R Nauck Matthias M Prokic Ivana I Pennell Craig E CE Pradhan Arund D AD Psaty Bruce M BM Raitakari Olli T OT Scott Robert A RA Skaaby Tea T Strauch Konstantin K Taylor Kent D KD Teumer Alexander A Uitterlinden Andre G AG Wu Ying Y Yao Jie J Walker Mark M North Kari E KE Kovacs Peter P Ikram M Arfan MA van Duijn Cornelia M CM Ridker Paul M PM Lye Stephen S Homuth Georg G Ingelsson Erik E Spector Tim D TD McKnight Barbara B Province Michael A MA Lehtimäki Terho T Adair Linda S LS Rotter Jerome I JI Reiner Alexander P AP Wilson James G JG Harris Tamara B TB Ripatti Samuli S Grallert Harald H Meigs James B JB Salomaa Veikko V Hansen Torben T Willems van Dijk Ko K Wareham Nicholas J NJ Grant Struan F A SFA Langenberg Claudia C Frayling Timothy M TM Lindgren Cecilia M CM Mohlke Karen L KL Leibel Rudolph L RL Loos Ruth J F RJF Kilpeläinen Tuomas O TO

Diabetes 20200911 12

Leptin influences food intake by informing the brain about the status of body fat stores. Rare <i>LEP</i> mutations associated with congenital leptin deficiency cause severe early-onset obesity that can be mitigated by administering leptin. However, the role of genetic regulation of leptin in polygenic obesity remains poorly understood. We performed an exome-based analysis in up to 57,232 individuals of diverse ancestries to identify genetic variants that influence adiposity-adjusted leptin conc ...[more]

PMID: 32917775

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Project description:OBJECTIVE: Pigment epithelium-derived factor (PEDF) belongs to the serpin family of peptidase inhibitors (serpin F1) and is among the most abundant glycoproteins secreted by adipocytes. In vitro and mouse in vivo data revealed PEDF as a candidate mediator of obesity-induced insulin resistance. Therefore, we assessed whether common genetic variation within the SERPINF1 locus contributes to adipose tissue-related prediabetic phenotypes in humans. SUBJECTS/METHODS: A population of 1,974 White European individuals at increased risk for type 2 diabetes was characterized by an oral glucose tolerance test with glucose and insulin measurements (1,409 leptin measurements) and genotyped for five tagging SNPs covering 100% of common genetic variation (minor allele frequency ? 0.05) in the SERPINF1 locus. In addition, a subgroup of 486 subjects underwent a hyperinsulinaemic-euglycaemic clamp and a subgroup of 340 magnetic resonance imaging (MRI) and spectroscopy (MRS). RESULTS: After adjustment for gender and age and Bonferroni correction for the number of SNPs tested, SNP rs12603825 revealed significant association with MRI-derived total adipose tissue mass (p?=?0.0094) and fasting leptin concentrations (p?=?0.0035) as well as nominal associations with bioelectrical impedance-derived percentage of body fat (p?=?0.0182) and clamp-derived insulin sensitivity (p?=?0.0251). The association with insulin sensitivity was completely abolished by additional adjustment for body fat (p?=?0.8). Moreover, the fat mass-increasing allele of SNP rs12603825 was significantly associated with elevated fasting PEDF concentrations (p?=?0.0436), and the PEDF levels were robustly and positively associated with all body fat parameters measured and with fasting leptin concentrations (p<0.0001, all). CONCLUSION: In humans at increased risk for type 2 diabetes, a functional common genetic variant in the gene locus encoding PEDF contributes to overall body adiposity, obesity-related insulin resistance, and circulating leptin levels.

Dataset Information

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

Publications

Genetic Studies of Leptin Concentrations Implicate Leptin in the Regulation of Early Adiposity.

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