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

Agné Kulyté,Veroniqa Lundbäck,Cecilia M Lindgren,Jian'An Luan,Luca A Lotta,Claudia Langenberg,Peter Arner,Rona J Strawbridge,Ingrid Dahlman

doi:10.1016/j.molmet.2020.01.009

Abstract

ObjectivesLipolysis, 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. MethodsAdipocytes 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. ResultsOne 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. ConclusionsIn 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.

Highlights

Release of fatty acids through hydrolysis of triglycerides in fat cells plays a major role in energy homeostasis
Studies of monozygotic twins demonstrated a strong within-pair resemblance of spontaneous and catecholamine-stimulated lipolysis [11,12] and we reported that family history of type 2 diabetes is associated with increased spontaneous adipocyte lipolysis [13]
Spontaneous lipolysis was positively correlated with the fasting plasma levels of triglycerides, free fatty acids, insulin, and HOMA-IR as measures of systemic insulin resistance after adjusting for age and sex beta beta plasma triglycerides 0.30 plasma nonesterified 0.22 fatty acids

Summary

Introduction

Release of fatty acids through hydrolysis (lipolysis) of triglycerides in fat cells plays a major role in energy homeostasis. Human fat cells have spontaneous lipolytic activity [1]. Large cross-sectional studies show significant relationships between high spontaneous or low catecholaminestimulated lipolysis and a variety of metabolic conditions such as obesity and insulin resistance [4e6]. A recent prospective study demonstrated that subjects with high spontaneous lipolysis activity and low catecholamine-stimulated lipolysis had a markedly increased risk of future development of excess body fat, insulin resistance, and type 2 diabetes/glucose intolerance [7]. There is a strong genetic component to clinical traits of relevance to lipolysis, including body fat (measured by body mass index, BMI) [8], the location of stored lipids (as measured by waist-to-hip ratio (WHR) adjusted for BMI, WHRadjBMI) [9], and circulating triglyceride levels [10]. A recent large study on expression quantitative trait loci (eQTLs) in

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