RT Journal Article
T1 Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance.
A1 Lotta, Luca A
A1 Gulati, Pawan
A1 Day, Felix R
A1 Payne, Felicity
A1 Ongen, Halit
A1 van de Bunt, Martijn
A1 Gaulton, Kyle J
A1 Eicher, John D
A1 Sharp, Stephen J
A1 Luan, Jian'an
A1 De Lucia Rolfe, Emanuella
A1 Stewart, Isobel D
A1 Wheeler, Eleanor
A1 Willems, Sara M
A1 Adams, Claire
A1 Yaghootkar, Hanieh
A1 EPIC-InterAct Consortium, 
A1 Cambridge FPLD1 Consortium, 
A1 Forouhi, Nita G
A1 Khaw, Kay-Tee
A1 Johnson, Andrew D
A1 Semple, Robert K
A1 Frayling, Timothy
A1 Perry, John R B
A1 Dermitzakis, Emmanouil
A1 McCarthy, Mark I
A1 Barroso, Inês
A1 Wareham, Nicholas J
A1 Savage, David B
A1 Langenberg, Claudia
A1 O'Rahilly, Stephen
A1 Scott, Robert A
AB 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.
YR 2016
FD 2016-11-14
LK https://hdl.handle.net/10668/24638
UL https://hdl.handle.net/10668/24638
LA en
DS RISalud
RD Apr 6, 2025