Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits

Frode Norheim; Yehudit Hasin-Brumshtein; Laurent Vergnes; Karthickeyan Chella Krishnan; Calvin Pan; Marcus M Seldin; Simon T Hui; Margarete Mehrabian; Zhiqiang Zhou; Sonul Gupta; Brian W Parks; Axel Walch; Karen Reue; Susanna M Hofmann; Arthur P Arnold; Aldons J Lusis

doi:10.1016/j.cmet.2018.12.013

Gene-by-Sex Interactions in Mitochondrial Functions and Cardio-Metabolic Traits

Cell Metab. 2019 Apr 2;29(4):932-949.e4. doi: 10.1016/j.cmet.2018.12.013. Epub 2019 Jan 10.

Authors

Frode Norheim¹, Yehudit Hasin-Brumshtein², Laurent Vergnes³, Karthickeyan Chella Krishnan², Calvin Pan², Marcus M Seldin², Simon T Hui², Margarete Mehrabian², Zhiqiang Zhou², Sonul Gupta², Brian W Parks⁴, Axel Walch⁵, Karen Reue³, Susanna M Hofmann⁶, Arthur P Arnold⁷, Aldons J Lusis⁸

Affiliations

¹ Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Nutrition, Institute of Basic Medical Sciences, Faculty of Medicine, University of Oslo, Oslo, Norway.
² Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
³ Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA.
⁴ Department of Nutritional Sciences, University of Wisconsin-Madison, Madison, WI, USA.
⁵ Research Unit Analytical Pathology, Helmholtz Zentrum München, Neuherberg, Germany.
⁶ Institute of Diabetes and Regeneration Research, Helmholtz Zentrum Muenchen, German Research Center for Environmental Health (GmbH), Neuherberg, Germany; German Center for Diabetes Research (DZD), Neuherberg, München 80336, Germany; Medizinische Klinik und Poliklinik IV, Klinikum der Ludwig Maximilian Universität (LMU), Munich, Germany.
⁷ Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA, USA.
⁸ Department of Medicine/Division of Cardiology and Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Human Genetics, University of California, Los Angeles, Los Angeles, CA, USA; Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, CA, USA. Electronic address: jlusis@mednet.ucla.edu.

Abstract

We studied sex differences in over 50 cardio-metabolic traits in a panel of 100 diverse inbred strains of mice. The results clearly showed that the effects of sex on both clinical phenotypes and gene expression depend on the genetic background. In support of this, genetic loci associated with the traits frequently showed sex specificity. For example, Lyplal1, a gene implicated in human obesity, was shown to underlie a sex-specific locus for diet-induced obesity. Global gene expression analyses of tissues across the panel implicated adipose tissue "beiging" and mitochondrial functions in the sex differences. Isolated mitochondria showed gene-by-sex interactions in oxidative functions, such that some strains (C57BL/6J) showed similar function between sexes, whereas others (DBA/2J and A/J) showed increased function in females. Reduced adipose mitochondrial function in males as compared to females was associated with increased susceptibility to obesity and insulin resistance. Gonadectomy studies indicated that gonadal hormones acting in a tissue-specific manner were responsible in part for the sex differences.

Keywords: adipose tissue “browning”; gene-by-sex interactions; gonadectomy; hybrid mouse diversity panel; mitochondrial functions; sex differences; uncoupling protein-1.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adipose Tissue / metabolism
Adipose Tissue / pathology
Animals
Cardiovascular Diseases / metabolism*
Cardiovascular Diseases / pathology
Female
Insulin Resistance
Male
Mice
Mice, Inbred Strains
Mice, Transgenic
Mitochondria / metabolism*
Obesity / metabolism
Obesity / pathology
Phenotype
Principal Component Analysis
Sex Characteristics

Abstract

Publication types

MeSH terms

Grants and funding