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

Abstract

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 peroxisome proliferative activated-receptor-γ coactivator-1α (PGC-1α), a transcriptional coactivator of biogenesis, and BCL-2/ADENOVIRUS EIB 19-kDa interacting protein (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-1α heterozygote (LPGC-1α), and BNIP3 null mice were thermoneutral housed (29–31°C) and divided into three groups: sedentary-low-fat diet (LFD), 16 wk of (HFD), or 16 wk of HFD with VWR for the final 8 wk (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-1α females. Males required VWR to elicit mitochondrial adaptations that were inherently present in sedentary females including greater mitochondrial coupling control 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-1α 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-1α or BNIP3.

Mitochondrial Dysfunction in the Transition from NASH to HCC

“…In line with increased liver PGC-1α being beneficial in NAFLD, liver-specific overexpression of PGC-1α in Sprague Dawley male rats increases fatty acid oxidation and tricarboxylic acid (TCA) cycle activity in isolated liver mitochondria, and this was coupled with reduced hepatic and plasma triglycerides [73]. While hepatic PGC-1α is known to increase in a fasting liver to promote lipid catabolism, it is interesting to note that it also increases following acute exercise training in rodents [74,75,76,77]. McCoin et al investigated whether liver-specific hemizygous disruption of PGC-1α had an impact on hepatic mitochondrial adaptation (respiratory capacity, H 2 O 2 production, mitophagy) in male and female mice fed a high-fat diet (HFD) and whether exercise (voluntary wheel running) affected outcomes [77].…”

“…While hepatic PGC-1α is known to increase in a fasting liver to promote lipid catabolism, it is interesting to note that it also increases following acute exercise training in rodents [74,75,76,77]. McCoin et al investigated whether liver-specific hemizygous disruption of PGC-1α had an impact on hepatic mitochondrial adaptation (respiratory capacity, H 2 O 2 production, mitophagy) in male and female mice fed a high-fat diet (HFD) and whether exercise (voluntary wheel running) affected outcomes [77]. They note wild-type female mice have an inherent ability to increase hepatic mitochondrial function in response to the obesogenic challenge, while males need exercise to equally adapt their respiratory capacity.…”

Heat Treatment Improves Hepatic Mitochondrial Respiratory Efficiency via Mitochondrial Remodeling

“… 5 To this end, our group and others have shown that defects in mitochondrial quality control pathways, such as mitophagy (the targeted degradation of damaged mitochondria), increase the susceptibility to hepatic steatosis in preclinical rodent models. 6–9 While we have shown that treatments such as exercise can alter mitophagy and mitochondrial respiratory function during high-fat feeding, 9 alternative strategies that improve hepatic mitochondrial quality control and function and ameliorate steatosis are needed as contraindications can exist for exercise in certain patient populations. 10 One potential strategy that our group has explored to great effect in animals and primary hepatocytes is heat treatment (HT).…”

Breast cancer endocrine therapy exhausts adipocyte progenitors promoting weight gain and glucose intolerance

“…For all other complexes, neither TAM nor EWD treatment impacted protein content in either diet group (Supplemental Fig 3G-H). These data suggest that the liver phenotype observed in HFHS mice treated with TAM or EWD is not the product of direct action of TAM or EWD on hepatic mitochondria after 7 weeks of treatment; however, disruption of ER signaling is known to directly impact the liver in several studies 48,49 .…”