Cited by 249Genetic Mapping and Diversity in Plants and AnimalsGenetic Associations and EpidemiologyGenetic and phenotypic traits in livestock

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Genetic Architecture of Insulin Resistance in the Mouse

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Parks, Brian W., Sallam, Tamer, Mehrabian, Margarete, Psychogios, Nikolas, Hui, Simon T., Norheim, Frode, Castellani, Lawrence W., Rau, Christoph D., Pan, Calvin, Phun, Jennifer, Zhou, Zhenqi, Yang, Wen-Pin, Neuhaus, Isaac, Gargalovic, Peter S., Kirchgessner, Todd G., Graham, Mark, Lee, Richard, Tontonoz, Peter, Gerszten, Robert E., Hevener, Andrea L., Lusis, Aldons J.·2015·Cell Metabolism

DOI 10.1016/j.cmet.2015.01.002PMC PMC4349439

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Abstract

Insulin resistance (IR) is a complex trait with multiple genetic and environmental components. Confounded by large differences between the sexes, environment, and disease pathology, the genetic basis of IR has been difficult to dissect. Here we examine IR and related traits in a diverse population of more than 100 unique male and female inbred mouse strains after feeding a diet rich in fat and refined carbohydrates. Our results show dramatic variation in IR among strains of mice and widespread differences between sexes that are dependent on genotype. We uncover more than 15 genome-wide significant loci and validate a gene, Agpat5, associated with IR. We also integrate plasma metabolite levels and global gene expression from liver and adipose tissue to identify metabolite quantitative trait loci (mQTL) and expression QTL (eQTL), respectively. Our results provide a resource for analysis of interactions between diet, sex, and genetic background in IR.

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Authors: Parks, B. W., Sallam, T., Mehrabian, M., Psychogios, N., Hui, S. T., Norheim, F., Castellani, L. W., Rau, C. D., Pan, C., Phun, J., Zhou, Z., Yang, W.-P., Neuhaus, I., Gargalovic, P. S., Kirchgessner, T. G., Graham, M., Lee, R., Tontonoz, P., Gerszten, R. E., Hevener, A. L., & Lusis, A. J.
Affiliations: University of California, Los Angeles (US)
University of Oslo (NO)
Bristol-Myers Squibb (United States) (US)
Ionis Pharmaceuticals (United States) (US)
Howard Hughes Medical Institute (US)
Harvard University (US)
Corresponding author: Parks, Brian W.
Lusis, Aldons J.
ORCID: Parks, Brian W.
Sallam, Tamer
Mehrabian, Margarete
Hui, Simon T.
Norheim, Frode
Pan, Calvin
Zhou, Zhenqi
Gargalovic, Peter S.
Lee, Richard
Tontonoz, Peter
Gerszten, Robert E.
Hevener, Andrea L.
Lusis, Aldons J.
Venue: Cell Metabolism
Publisher: Elsevier BV
Published: 2015-02
Volume: 21
Issue: 2
Pages: 334-347
ISSN: 1550-4131 (ISSN-L)
DOI: 10.1016/j.cmet.2015.01.002
PMC: PMC4349439
OpenAlex: W2000653200
Cited by: 249
References: 53
Citations by year: 2026: 9 · 2025: 20 · 2024: 26 · 2023: 36 · 2022: 25 · 2021: 22 · 2020: 31 · 2019: 26 · 2018: 19 · 2017: 16 · 2016: 9 · 2015: 8
FWCI: 11.86
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 367 d)
Locations: Cell Metabolism (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
eScholarship (California Digital Library) (submittedVersion)
Funders: National Heart, Lung, and Blood Institute (K99HL123021, P01HL090553, HL28481, R01HL081572, R00HL123021, T32HL069766, P01HL028481)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK089109, P30DK041301, P30DK063491, R01DK081572)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007228)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
Keywords: insulin resistance, genetic architecture, inbred mouse strains, sex differences, metabolite quantitative trait loci, expression quantitative trait loci, hepatic gene expression, adipose tissue gene expression, high-fat high-carbohydrate diet, genetic background
MeSH terms: Animals, Dietary Carbohydrates, Female, Genotype, Insulin Resistance, Male, Mice, Inbred C3H, Mice, Inbred C57BL, Mice, Inbred DBA, Genetic Variation, 1-Acylglycerol-3-Phosphate O-Acyltransferase, Mice, Diet, High-Fat

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Genetic Architecture of Insulin Resistance in the Mouse

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