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

• Published in: Cell metabolism Vol. 29; no. 4; pp. 932 - 949.e4
• Main Authors: Norheim, Frode, Hasin-Brumshtein, Yehudit, Vergnes, Laurent, Chella Krishnan, Karthickeyan, Pan, Calvin, Seldin, Marcus M., Hui, Simon T., Mehrabian, Margarete, Zhou, Zhiqiang, Gupta, Sonul, Parks, Brian W., Walch, Axel, Reue, Karen, Hofmann, Susanna M., Arnold, Arthur P., Lusis, Aldons J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 02-04-2019
• Subjects: Adipose Tissue - metabolism; Adipose Tissue - pathology; adipose tissue “browning”; Animals; Cardiovascular Diseases - metabolism; Cardiovascular Diseases - pathology; Female; gene-by-sex interactions; gonadectomy; hybrid mouse diversity panel; Insulin Resistance; Male; Mice; Mice, Inbred Strains; Mice, Transgenic; Mitochondria - metabolism; mitochondrial functions; Obesity - metabolism; Obesity - pathology; Phenotype; Principal Component Analysis; Sex Characteristics; sex differences; uncoupling protein-1; gene-by-sex interactions; adipose tissue “browning”; hybrid mouse diversity panel; uncoupling protein-1; mitochondrial functions; gonadectomy; sex differences
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2018.12.013

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.
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•Sex differences in phenotype and gene expression depend upon genetic background•The gene Lypla1 impacts obesity in a sex-specific manner•Functional analyses reveal sex differences for adipose tissue beiging•Adipose mitochondrial function depends upon gene-by-sex interactions
Norheim and colleagues use the hybrid mouse diversity panel to comprehensively address the role of sex, and its interaction with genetic background, on cardio-metabolic phenotypes and gene expression. They discover a sex-specific obesity locus for Lyplal1, reveal sex-specific regulation of adipose tissue beiging, and find gene-by-sex interactions for mitochondrial function.