Genetic and sex-specific regulation of mitochondrial function in gonadal and inguinal adipose tissue

Sex differences in adipose tissue impact metabolic health, but the underlying molecular mechanisms remain unclear. We previously identified a female-specific chr17 trans-eQTL hotspot regulating mitochondrial gene expression in gonadal white adipose tissue (gWAT). Here, we tested whether iWAT contributes comparably to sex differences in mitochondrial function and futile cycling.

We analyzed iWAT and gWAT from male and female mice across 58 genetically diverse Hybrid Mouse Diversity Panel (HMDP) strains fed a high-fat, high-sucrose diet. We assessed mitochondrial DNA (mtDNA), oxidative phosphorylation (OXPHOS) and futile cycle gene expression, performed genetic mapping, and measured respiration.

In gWAT, females showed higher mtDNA, OXPHOS expression, and a female-specific chr17 trans-eQTL, correlating with metabolic traits. In contrast, iWAT lacked this hotspot and showed higher mtDNA, OXPHOS expression, and respiration in males. Lipid cycling genes (Lipe, Mgll, Pnpla2) were elevated in male iWAT, while Mpc1, Mpc2, and Pck1 were enriched in female gWAT. Ucp1 was higher in female gWAT but not sex-biased in iWAT. Alpl (TNAP), key creatine cycling gene, was upregulated in females in both depots, particularly in iWAT.

Female gWAT shows genetically driven mitochondrial regulation linked to metabolic protection, whereas male iWAT has higher mitochondrial content, OXPHOS expression, and respiration. Elevated lipolytic enzymes in male iWAT suggest greater FFA release, while higher pyruvate import and glyceroneogenesis genes in female gWAT favor FFA recycling. Alpl upregulation in females indicates sex-biased UCP1-independent thermogenesis. These depot- and sex-specific signatures reflect distinct metabolic strategies and highlight the need to consider both in adipose research.