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

2.50
Hdl Handle:
http://hdl.handle.net/11287/620141
Title:
Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance
Authors:
Lotta, L. A. [et al]; Ellard, Sian ( 0000-0002-7620-5526 )
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.
Citation:
Integrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nature Genetics 2017 Jan;49(1):17-26
Publisher:
Nature
Journal:
Nature Genetics
Issue Date:
Jan-2017
URI:
http://hdl.handle.net/11287/620141
DOI:
10.1038/ng.3714
Additional Links:
http://dx.doi.org/10.1038/ng.3714
Type:
Journal Article
Language:
en
Description:
Sian Ellard is listed as a collaborator on this article.
Appears in Collections:
Molecular Genetics; 2017 RD&E publications

Full metadata record

DC FieldValue Language
dc.contributor.authorLotta, L. A. [et al]en
dc.contributor.authorEllard, Sianen
dc.date.accessioned2017-01-05T16:06:20Z-
dc.date.available2017-01-05T16:06:20Z-
dc.date.issued2017-01-
dc.identifier.citationIntegrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistance. Nature Genetics 2017 Jan;49(1):17-26en
dc.identifier.doi10.1038/ng.3714-
dc.identifier.urihttp://hdl.handle.net/11287/620141-
dc.descriptionSian Ellard is listed as a collaborator on this article.en
dc.description.abstractInsulin 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.en
dc.language.isoenen
dc.publisherNatureen
dc.relation.urlhttp://dx.doi.org/10.1038/ng.3714en
dc.rightsArchived with thanks to Nature Genetics.en
dc.subjectWessex Classification Subject Headings::Oncology. Pathology.::Geneticsen
dc.titleIntegrative genomic analysis implicates limited peripheral adipose storage capacity in the pathogenesis of human insulin resistanceen
dc.typeJournal Articleen
dc.identifier.journalNature Geneticsen
dc.type.versionPublisheden
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