Sex-Specific Genetic Regulation Of Adipose Mitochondria And Their Relationship To Metabolic Syndrome

Background and Objectives Mitochondria plays a major role in the pathophysiology of complex metabolic traits such as obesity, insulin resistance and fatty liver disease. However, the exact causal relationship between mitochondrial function and these traits is not completely understood. Similarly, sex differences in susceptibility to metabolic phenotypes have been amply described in mice, humans and other species, with females generally exhibiting a beneficial metabolic profile. Yet, the vast majority of previous studies examined sex differences in phenotypes or gene expression in isolation, generating trait or tissue specific results without putting them in context of genetic variation. Methods To understand the nature of the sex differences and causal relationships, we examined genetic factors contributing to mitochondrial function using a mouse reference population that were extensively phenotyped called hybrid mouse diversity panel. Results We identified a genetic locus on mouse chromosome 17 that controls mitochondria levels and function in adipose tissue in a sex- and tissue-specific manner. It regulates the expression of at least 89 mitochondrial genes, many of them related to oxidative phosphorylation, as well as mitochondrial DNA levels, in female but not male mice. Overexpression studies indicate that the effects of the locus are mediated by the Ndufv2 gene that encodes a subunit of the mitochondrial complex-I. The gene is activated by gonadal hormones and is regulated in cis only in females. Conclusion We report that adipose mitochondria are regulated by both genetic variation and sex hormones and that high levels are an important determinant of metabolic syndrome traits.