Format

Send to

Choose Destination
Nat Genet. 2017 Jan;49(1):17-26. doi: 10.1038/ng.3714. Epub 2016 Nov 14.

Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.

Author information

1
MRC Epidemiology Unit, University of Cambridge, Cambridge, UK.
2
Metabolic Research Laboratories, Institute of Metabolic Science, University of Cambridge, Cambridge, UK.
3
Wellcome Trust Sanger Institute, Hinxton, UK.
4
Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
5
Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, UK.
6
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
7
Department of Pediatrics, University of California at San Diego, La Jolla, California, USA.
8
Population Sciences Branch, Division of Intramural Research, National Heart, Lung, and Blood Institute, Bethesda, Maryland, USA.
9
Genetics of Complex Traits, Institute of Biomedical and Clinical Science, University of Exeter Medical School, Royal Devon and Exeter Hospital, Exeter, UK.
10
Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.

Abstract

Insulin resistance is a key mediator of obesity-related cardiometabolic disease, yet the mechanisms underlying this link remain obscure. Using an integrative genomic approach, we identify 53 genomic regions associated with insulin resistance phenotypes (higher fasting insulin levels adjusted for BMI, lower HDL cholesterol levels and higher triglyceride levels) and provide evidence that their link with higher cardiometabolic risk is underpinned by an association with lower adipose mass in peripheral compartments. Using these 53 loci, we show a polygenic contribution to familial partial lipodystrophy type 1, a severe form of insulin resistance, and highlight shared molecular mechanisms in common/mild and rare/severe insulin resistance. Population-level genetic analyses combined with experiments in cellular models implicate CCDC92, DNAH10 and L3MBTL3 as previously unrecognized molecules influencing adipocyte differentiation. Our findings support the notion that limited storage capacity of peripheral adipose tissue is an important etiological component in insulin-resistant cardiometabolic disease and highlight genes and mechanisms underpinning this link.

PMID:
27841877
PMCID:
PMC5774584
DOI:
10.1038/ng.3714
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Nature Publishing Group Icon for PubMed Central
Loading ...
Support Center