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

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.

SUBMITTER: Lotta LA

PROVIDER: S-EPMC5774584 | biostudies-literature | 2017 Jan

REPOSITORIES: biostudies-literature

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

Lotta Luca A LA Gulati Pawan P Day Felix R FR Payne Felicity F Ongen Halit H van de Bunt Martijn M Gaulton Kyle J KJ Eicher John D JD Sharp Stephen J SJ Luan Jian'an J De Lucia Rolfe Emanuella E Stewart Isobel D ID Wheeler Eleanor E Willems Sara M SM Adams Claire C Yaghootkar Hanieh H Forouhi Nita G NG Khaw Kay-Tee KT Johnson Andrew D AD Semple Robert K RK Frayling Timothy T Perry John R B JR Dermitzakis Emmanouil E McCarthy Mark I MI Barroso Inês I Wareham Nicholas J NJ Savage David B DB Langenberg Claudia C O'Rahilly Stephen S Scott Robert A RA

Nature genetics 20161114 1

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 periphe ...[more]

PMID: 27841877

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

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

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