title: Genetic architecture of insulin resistance in the mouse.
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.
authors: 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.
authors: Brian W
authors: BW
authors: Parks
authors: 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.
authors: Tamer
authors: T
authors: Sallam
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Margarete
authors: M
authors: Mehrabian
authors: Cardiovascular Research Center and Cardiology Division, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Nikolas
authors: N
authors: Psychogios
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Simon T
authors: ST
authors: Hui
authors: Department of Nutrition, Faculty of Medicine, Institute of Basic Medical Sciences, University of Oslo, 0317 Oslo, Norway.
authors: Frode
authors: F
authors: Norheim
authors: Division of Cardiology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Lawrence W
authors: LW
authors: Castellani
authors: 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.
authors: Christoph D
authors: CD
authors: Rau
authors: Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Calvin
authors: C
authors: Pan
authors: Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Jennifer
authors: J
authors: Phun
authors: Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Zhenqi
authors: Z
authors: Zhou
authors: Department of Applied Genomics, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Wen-Pin
authors: WP
authors: Yang
authors: Department of Applied Genomics, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Isaac
authors: I
authors: Neuhaus
authors: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Peter S
authors: PS
authors: Gargalovic
authors: Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb, Princeton, NJ 08543, USA.
authors: Todd G
authors: TG
authors: Kirchgessner
authors: Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
authors: Mark
authors: M
authors: Graham
authors: Isis Pharmaceuticals, Carlsbad, CA 92008, USA.
authors: Richard
authors: R
authors: Lee
authors: 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.
authors: Peter
authors: P
authors: Tontonoz
authors: Cardiovascular Research Center and Cardiology Division, Harvard Medical School, Massachusetts General Hospital, Boston, MA 02114, USA.
authors: Robert E
authors: RE
authors: Gerszten
authors: Division of Endocrinology, Diabetes and Hypertension, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors: Andrea L
authors: AL
authors: Hevener
authors: 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.
authors: Aldons J
authors: AJ
authors: Lusis
mesh_terms: D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D059305:Diet, High-Fat; D004040:Dietary Carbohydrates; D005260:Female; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA
chemical_list: D004040:Dietary Carbohydrates; D051103:1-Acylglycerol-3-Phosphate O-Acyltransferase
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