Estradiol treatment and exercise improve hepatic mitochondrial outcomes in mice following ovariectomy

Abstract

We recently reported that female mice have increased hepatic mitochondrial respiratory capacity, and differential responses to exercise compared to male mice. Here we sought to determine the role of estrogen in the enhanced hepatic mitochondrial function found in female mice. Female C57BL mice (n= 4–6 per group) were randomly assigned to sham surgery (Sham), ovariectomy (OVX), or OVX plus estradiol replacement therapy from ~8 to 13 weeks of age. Half of the mice in each group were assigned to sedentary (SED) or voluntary wheel running (VWR). All mice had ad libitum access to high‐fat diet (HFD). We assessed isolated hepatic mitochondrial respiratory capacity using the Oroboros O2k with both pyruvate and palmityl‐carnitine as substrates. VWR reduced basal respiratory capacity of palmityl‐carnitine across all treatment groups. The OVX+Est group displayed increased State 3 respiratory capacity with pyruvate. Interestingly, in the absence of estrogen (OVX), both VWR and exogenous estradiol treatment independently improve the coupling control ratio (Basal/State 3: representative of coupling efficiency) and leak control ratio (Basal/Uncoupled: indicative of free ETS capacity) with pyruvate. We further assessed liver whole homogenate electron transport chain (ETC) protein content and found independent and combined effects of estradiol and exercise that were complex‐specific. The OVX group had a unique compensatory effect of increased Complex I protein with VWR, that was diminished with estradiol add‐back. Further investigation of treatment effects for complexes I‐IV, suggest that statistical differences are driven by the OVX. Interestingly, the sedentary OVX+Est group presented similarly to the Sham VWR group. In conclusion, these data suggest that ovariectomy leads to reduced hepatic mitochondrial respiratory control, and that estradiol replacement and modest exercise can aid in rescuing this phenotype.Support or Funding InformationThis work was funded by VA Merit Review: 1I01BX002567‐01This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.