Genome-wide association study of adipocyte lipolysis in the GENetics of Adipocyte Lipolysis (GENiAL) cohort

Kulyte, A., Lundback, V., Lindgren, C., Luan, J.'a., Lotta, L. A., Lagenberg, C., Arner, P., Strawbridge, R. J. and Dahlman, I. (2020) Genome-wide association study of adipocyte lipolysis in the GENetics of Adipocyte Lipolysis (GENiAL) cohort. Molecular Metabolism, 34, pp. 85-96. (doi: 10.1016/j.molmet.2020.01.009) (PMCID:PMC7021539)

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Abstract

Objectives: Lipolysis, hydrolysis of triglycerides to fatty acids in adipocytes, is tightly regulated, poorly understood, and, if perturbed, can lead to metabolic diseases including obesity and type 2 diabetes. The goal of this study was to identify the genetic regulators of lipolysis and elucidate their molecular mechanisms. Methods: Adipocytes from abdominal subcutaneous adipose tissue biopsies were isolated and were incubated without (spontaneous lipolysis) or with a catecholamine (stimulated lipolysis) to analyze lipolysis. DNA was extracted and genome-wide genotyping and imputation conducted. After quality control, 939 samples with genetic and lipolysis data were available. Genome-wide association studies of spontaneous and stimulated lipolysis were conducted. Subsequent in vitro gene expression analyses were used to identify candidate genes and explore their regulation of adipose tissue biology. Results: One locus on chromosome 19 demonstrated genome-wide significance with spontaneous lipolysis. 60 loci showed suggestive associations with spontaneous or stimulated lipolysis, of which many influenced both traits. In the chromosome 19 locus, only HIF3A was expressed in the adipocytes and displayed genotype-dependent gene expression. HIF3A knockdown in vitro increased lipolysis and the expression of key lipolysis-regulating genes. Conclusions: In conclusion, we identified a genetic regulator of spontaneous lipolysis and provided evidence of HIF3A as a novel key regulator of lipolysis in subcutaneous adipocytes as the mechanism through which the locus influences adipose tissue biology.

Item Type:Articles
Additional Information:RJS is supported by a UKRI Innovation at HDR-UK Fellowship (MR/S003061/1). CML is supported by the Li Ka Shing Foundation; the NIHR Biomedical Research Center, Oxford; Widenlife; the NIH (5P50HD028138-27); and has collaborated with Novo Nordisk and Bayer in research, and in accordance with the policy of the University of Oxford, did not accept any personal payment. This study was supported by the Strategic Research Program in Diabetes at Karolinska Institute, Swedish Research Council, Novo Nordisk Foundation, and the Swedish Diabetes Association.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Strawbridge, Dr Rona
Creator Roles:
Strawbridge, R.Writing – original draft
Authors: Kulyte, A., Lundback, V., Lindgren, C., Luan, J.'a., Lotta, L. A., Lagenberg, C., Arner, P., Strawbridge, R. J., and Dahlman, I.
College/School:College of Medical Veterinary and Life Sciences > Institute of Health and Wellbeing > Mental Health and Wellbeing
Journal Name:Molecular Metabolism
Publisher:Elsevier
ISSN:2212-8778
ISSN (Online):2212-8778
Published Online:25 January 2020
Copyright Holders:Copyright © 2020 The Authors
First Published:First published in Molecular Metabolism 34:85-96
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
302131Understanding the excess risk of cardiometabolic disease in individuals with serious mental illnessJill PellMedical Research Council (MRC)MR/S003061/1HW - Public Health