Shared genetic loci for body fat storage and adipocyte lipolysis in humans

Kulyté, A., Lundbäck, V., Arner, P., Strawbridge, R. and Dahlman, I. (2022) Shared genetic loci for body fat storage and adipocyte lipolysis in humans. Scientific Reports, 12, 3666. (doi: 10.1038/s41598-022-07291-4) (PMID:35256633) (PMCID:PMC8901764)

Abstract

Total body fat and central fat distribution are heritable traits and well-established predictors of adverse metabolic outcomes. Lipolysis is the process responsible for the hydrolysis of triacylglycerols stored in adipocytes. To increase our understanding of the genetic regulation of body fat distribution and total body fat, we set out to determine if genetic variants associated with body mass index (BMI) or waist-hip-ratio adjusted for BMI (WHRadjBMI) in genome-wide association studies (GWAS) mediate their effect by influencing adipocyte lipolysis. We utilized data from the recent GWAS of spontaneous and isoprenaline-stimulated lipolysis in the unique GENetics of Adipocyte Lipolysis (GENiAL) cohort. GENiAL consists of 939 participants who have undergone abdominal subcutaneous adipose biopsy for the determination of spontaneous and isoprenaline-stimulated lipolysis in adipocytes. We report 11 BMI and 15 WHRadjBMI loci with SNPs displaying nominal association with lipolysis and allele-dependent gene expression in adipose tissue according to in silico analysis. Functional evaluation of candidate genes in these loci by small interfering RNAs (siRNA)-mediated knock-down in adipose-derived stem cells identified ZNF436 and NUP85 as intrinsic regulators of lipolysis consistent with the associations observed in the clinical cohorts. Furthermore, candidate genes in another BMI-locus (STX17) and two more WHRadjBMI loci (NID2, GGA3, GRB2) control lipolysis alone, or in conjunction with lipid storage, and may hereby be involved in genetic control of body fat. The findings expand our understanding of how genetic variants mediate their impact on the complex traits of fat storage and distribution.

• Item Type: Articles
• Additional Information: RJS is supported by a the UKRI innovation-HDR-UK Fellowship (MR/S003061/1). ID is supported by the Strategic Research Program in Diabetes at Karolinska Institutet (Genetic and long-term epigenetic studies of changes in adipose function), Swedish Research Council (2019-00997), Novo Nordisk foundation (NNF200C0063582), and the Swedish Diabetes Association (DIA2019-407). PA is supported by the Strategic Research Program in Diabetes at Karolinska Institutet for studies of human fat cell function.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Strawbridge, Dr Rona
• Authors: Kulyté, A., Lundbäck, V., Arner, P., Strawbridge, R., and Dahlman, I.
• College/School: College of Medical Veterinary and Life Sciences > School of Health & Wellbeing > Mental Health and Wellbeing
• Journal Name: Scientific Reports
• Publisher: Nature Research
• ISSN: 2045-2322
• ISSN (Online): 2045-2322
• Copyright Holders: Copyright © 2022 The Author(s)
• First Published: First published in Scientific Reports 12: 3666
• Publisher Policy: Reproduced under a Creative Commons License

Project Code	Award No	Project Name	Principal Investigator	Funder's Name	Funder Ref	Lead Dept
302131		Understanding the excess risk of cardiometabolic disease in individuals with serious mental illness	Jill Pell	Medical Research Council (MRC)	MR/S003061/1	HW - Public Health