Sex‐Dependent Murine Hepatic Mitochondrial and Mitophagy Responses to High‐Fat Diet and Exercise

Abstract

Excessive accumulation of hepatic fat (steatosis) is closely associated with obesity and hepatic insulin resistance, a critical factor for the development of type 2 diabetes. Exercise is a therapeutic that mitigates hepatic steatosis putatively through enhanced mitochondrial function and quality, but sex specific differences are unknown. Here we examined if a high fat diet (HFD) elicited sex‐specific reductions in hepatic mitochondrial respiration and mitochondrial recycling (autophagy/mitophagy) pathways and whether exercise (voluntary wheel running [VWR]) restored these impingements. Male and female wild type (WT, C57BL/6J) mice (n=6–7 per sex, per treatment) housed at thermoneutrality (~80°F) were fed low fat diet (LFD) or HFD (45%kcal fat) for 16 weeks with or without access to VWR for the final 8 weeks. Female mice had significantly reduced hepatic triacylglycerol (TAG) compared to males (p<0.0001) and both sexes showed resistance to increases in TAG with HFD, potentially due to thermoneutral housing inducing higher TAG on a control diet. There was a dose‐dependent increase in maximal state 3 (ADP stimulated) respiratory capacity with HFD and HFD+VWR that was potentiated in females. HFD elicited an increase in H2O2 in males that was reduced with exercise while females had reduced mitochondrial H2O2 production in both conditions. Interestingly, neither glutathione (GSH), glutathione disulfide (GSSG) or the GSH:GSSG ratio, markers of oxidative stress, were different between the groups. Males had a consistent reduction in mitochondrial complex I‐V expression with HFD+VWR. Females had reduced expression of complex I with HFD and HFD+VWR but otherwise retained expression of complexes II‐V. Citrate synthase, a marker of hepatic mitochondrial content, was reduced by HFD in both males and females. However, HFD+VWR further reduced citrate synthase in males but restored activity in females to the level of the LFD cohort. Since mitochondrial content is regulated by mitophagy proteins, we examined the mitophagy regulating BCL2/adenovirus E1B 19 kDa protein‐interacting protein 3 (BNIP3) and Parkin proteins. Males had reduced BNIP3 expression on the LFD that was increased with HFD. HFD elicited no change in females, however, HFD+VWR drastically reduced BNIP3 levels in both sexes. Parkin was unchanged with HFD in both sexes yet had divergent responses with HFD+VWR as males had reduced expression and female expression increased. Overall, these data show sex‐specific hepatic triglyceride, mitochondrial, and mitophagy responses to HFD and exercise and provide cautionary evidence of studying hepatic steatosis in single sex models.Support or Funding InformationFunded by: Veterans Affairs Merit Review; 1I01BX002567‐01 (JPT), KUMC Biomedical Research Training Program (CSM), K‐INBRE grant number P20 GM103418 (CSM), CTSA grant from NCATS awarded to the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute (# TL1TR002368) (CSM)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.