Genetic architecture of insulin resistance in the mouse

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

doi:10.1016/j.cmet.2015.01.002

Genetic architecture of insulin resistance in the mouse

Cell Metab. 2015 Feb 3;21(2):334-347. doi: 10.1016/j.cmet.2015.01.002.

Authors

Brian W Parks¹, Tamer Sallam², Margarete Mehrabian³, Nikolas Psychogios⁴, Simon T Hui³, Frode Norheim⁵, Lawrence W Castellani³, Christoph D Rau⁶, Calvin Pan⁷, Jennifer Phun⁸, Zhenqi Zhou⁸, Wen-Pin Yang⁹, Isaac Neuhaus⁹, Peter S Gargalovic¹⁰, Todd G Kirchgessner¹⁰, Mark Graham¹¹, Richard Lee¹¹, Peter Tontonoz¹², Robert E Gerszten⁴, Andrea L Hevener⁸, Aldons J Lusis¹³

Affiliations

¹ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: bparks@mednet.ucla.edu.
² Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
³ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁴ Cardiovascular Research Center and Cardiology Division, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
⁵ Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
⁶ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁷ Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁸ Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
⁹ Department of Applied Genomics, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
¹⁰ Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
¹¹ Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
¹² Department of Pathology and Laboratory Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Howard Hughes Medical Institute, University of California, Los Angeles, Los Angeles, CA 90095, USA.
¹³ Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Microbiology, Immunology & Molecular Genetics, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: jlusis@mednet.ucla.edu.

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

1-Acylglycerol-3-Phosphate O-Acyltransferase / genetics
1-Acylglycerol-3-Phosphate O-Acyltransferase / metabolism
Animals
Diet, High-Fat
Dietary Carbohydrates
Female
Genetic Variation / genetics
Genotype
Insulin Resistance / genetics*
Male
Mice
Mice, Inbred C3H
Mice, Inbred C57BL
Mice, Inbred DBA

Substances

Dietary Carbohydrates
1-Acylglycerol-3-Phosphate O-Acyltransferase

Abstract

Publication types

MeSH terms

Substances

Grants and funding