Gene-by-sex interactions in mitochondrial functions and tissue-specific gene expression in cardio-metabolic traits

We report a multi-omic study of sex differences and gene-by-sex interactions across a panel of 100 inbred strains of mice (the Hybrid Mouse Diversity Panel, HMDP), with a focus on metabolic and cardiovascular traits. For all traits examined, including obesity, insulin resistance, fatty liver, atherosclerosis, and gut microbiota composition, sex differences were influenced by genetic background. Loci identified by genome-wide association studies (GWAS) of the traits were frequently influenced by sex. Lyplal1, a gene implicated in human obesity, was shown to underlie a sex-specific locus for diet induced obesity. Many of the sex-dependent traits showed interdependencies as judged by correlation and shared gene expression patterns, indicating higher order regulation. Global gene expression analyses of tissues across the HMDP indicated that sex differences in mitochondrial functions in adipose contributed to many of the traits. Consistent with this, we observed that females tended to be more resistant to the adverse effects of a high fat diet, with smaller adipocytes and increased “browning” of white adipose tissue as compared to males. Sex-specific differences in mitochondrial activity were confirmed by examining respiration of isolated mitochondria. Gonadectomy experiments revealed thousands of genes influenced by sex hormones. In liver, a tissue exhibiting particularly strong differences in gene expression between tissues, sex hormones appeared to be the primary driver of the differences, whereas in adipose organizational effects of sex appeared to be more important. Overall design: Sixteen male and sixteen female C57BL/6J were purchased from The Jackson Laboratory (Bar Harbor). Mice were either maintained on a chow diet (Ralston Purina Company) or placed on an HF/HS diet (Research Diets D12266B) at 8 weeks of age until 16 weeks of age. At 6 weeks of age the mice were gonadectomized under isoflurane anesthesia. Scrotal regions of male mice were bilaterally incised, testes removed, and the incisions closed with wound clips. Ovaries of female mice were removed through an incision just below the rib cage. There were four mice per group. The muscle layer was sutured, and the incision closed with wound clips. In sham-operated control mice, incisions were made and closed as described above. The gonads were briefly manipulated, but remained intact. Gonadal fat and liver samples were taken for RNASeq expression profiling.

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Norheim F, Hasin-Brumshtein Y, Vergnes L, Chella Krishnan K, Pan C, Seldin MM, Hui ST, Mehrabian M, Zhou Z, Gupta S, Parks BW, Walch A, Reue K, Hofmann SM, Arnold AP, Lusis AJ