Sex modulates hepatic mitochondrial adaptations to high fat diet and physical activity.

The impact of sexual dimorphism and mitophagy on hepatic mitochondrial adaptations during the treatment of steatosis with physical activity are largely unknown. Here, we tested if deficiencies in liver-specific PGC-1a, a transcriptional co-activator of biogenesis, and BNIP3, a mitophagy regulator, would impact hepatic mitochondrial adaptations (respiratory capacity, H2O2 production, mitophagy) to a high-fat diet (HFD) and HFD plus physical activity via voluntary wheel running (VWR) in both sexes. Male and female wild type (WT), liver-specific PGC-1a heterozygote (LPGC-1a) and BNIP3 null mice were thermoneutral housed (29-31°C) and divided into three groups: sedentary - low fat diet (LFD), 16 weeks of (HFD), or 16 weeks of HFD with VWR for the final 8 weeks (HFD+VWR) (n=5-7/sex/group). HFD did not impair mitochondrial respiratory capacity or coupling in any group, however HFD+VWR significantly increased maximal respiratory capacity only in WT and PGC-1a females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling efficiency and reduced H2O2 production. Females had overall reduced markers of mitophagy, steatosis, and liver damage. Steatosis and markers of liver injury were present in sedentary male mice on the HFD and were effectively reduced with VWR despite no resolution of steatosis. Overall, reductions in PGC-1a and loss of BNIP3 only modestly impacted mitochondrial adaptations to HFD and HFD+VWR with the biggest effect seen in BNIP3 females. In conclusion, hepatic mitochondrial adaptations to HFD and treatment of HFD-induced steatosis with VWR are more dependent on sex than PGC-1a or BNIP3.