Non-acholic fatty liver disease, or hepatic steatosis, is the most common liver disorder affecting the western world and currently has no pharmacologic cure. Thus, many investigations have focused on alternative strategies to treat or prevent hepatic steatosis. Our laboratory has shown that chronic heat treatment (HT) mitigates glucose intolerance, insulin resistance, and hepatic steatosis in rodent models of obesity. Here, we investigate the direct bioenergetic mechanism(s) surrounding the metabolic effects of HT on hepatic mitochondria. Utilizing mitochondrial proteomics and respiratory function assays, we show that one bout of acute HT (42 °C for 20min) in male C57Bl/6J mice (n = 6/group) triggers a hepatic mitochondrial heat shock response resulting in acute reductions in respiratory capacity, degradation of key mitochondrial enzymes, and induction of mitophagy via mitochondrial ubiquitination. We also show that chronic bouts of HT and recurrent activation of the heat shock response enhances mitochondrial quality and respiratory function via compensatory adaptations in mitochondrial organization, gene expression, and transport even during 4weeks of high-fat feeding (n = 6/group). Finally, utilizing a liver specific heat shock protein 72 (HSP72) knockout model, we are the first to show that HSP72, a protein putatively driving the HT metabolic response, does not play a significant role in the hepatic mitochondrial adaptation to acute or chronic HT. However, HSP72 is required for the reductions in blood glucose observed with chronic HT. Our data are the first to suggest that chronic HT 1) improves hepatic mitochondrial respiratory efficiency via mitochondrial remodeling and 2) reduces blood glucose in a hepatic HSP72-dependent manner.

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Exercise is critical for improving metabolic health and putatively maintains or enhances mitochondrial quality control in metabolic tissues. While previous work has shown exercise elicits hepatic mitochondrial biogenesis, it is unknown if acute exercise activates hepatic mitophagy, the selective degradation of damaged or low-functioning mitochondria. We tested if an acute bout of treadmill running increased hepatic mitophagic flux both immediately after and 2 hours post-exercise in 15-24-week-old C57BL/6J female mice. Acute exercise did not significantly increase markers of autophagic flux, however, mitophagic flux was activated 2 hours post-treadmill running as measured by accumulation of both LC3-II and p62 in isolated mitochondria in the presence of leupeptin, an inhibitor of autophagosome degradation. Further, mitochondrial associated ubiquitin, which recruits the autophagy receptor protein p62, was also significantly increased at 2 hours. Further examination via western blot and proteomics analysis revealed acute exercise elicits a time-dependent, dynamic activation of mitophagy pathways. Moreover, the results suggest that exercise induced hepatic mitophagy is likely mediated by both poly-ubiquitination and receptor mediated signaling pathways. Overall, we provide evidence that acute exercise activates hepatic mitophagic flux while also revealing specific receptor-mediated proteins by which exercise maintains mitochondrial quality control in the liver.

Exercise powerfully increases energy metabolism and substrate flux in tissues, a process reliant on dramatic changes in mitochondrial energetics. Liver mitochondria play a multi-factorial role during exercise to fuel hepatic...

BackgroundAerobic capacity (VO2 max) strongly influences biological functions including both liver and brain function. Low aerobic capacity has far reaching impacts with both increased risk of non‐alcoholic fatty liver disease (NAFLD) and Alzheimer’s disease (AD). Previous work has shown that poor liver function was associated with decreased cognitive function and increased risk of AD. In addition, diet and lipid metabolism play a critical role in brain health, however, the full relationship between these factors and AD risk needs to be elucidated.MethodWe assessed brain mitochondrial function and AD pathology in rats selectively bred for aerobic capacity (low‐capacity runners or high capacity runners, bred over 43 generations). Mitochondrial function was assessed using Seahorse XF technology and spectrophotometric Vmax assays. Phosphorylated tau and Aβ levels were analyzed using western blotting and ELISAs. We assessed outcomes at 12, 18, 24, and 28 months. A separate cohort of rats were fed a low‐fat diet (LFD), high fat diet (HFD), or high fat diet with bile acid sequestrant (HFD+BA) and followed from age 6 to 12 months. Barnes and Y‐maze were performed to measure cognitive outcomes. MRI/MRS was completed to measure hippocampal volume and neurochemical profiles.ResultMitochondrial function parameters were different between groups and with different diets in both brain and liver. Overall LCR animals had reduced brain mitochondrial function and reduced resilience with long term HFD. LCR rats had increased phosphorylated tau levels. Female rats with a low intrinsic aerobic capacity (LCR) have significantly higher levels of Aβ42 when compared to rats with a high intrinsic aerobic capacity (HCR). LCR rats performed worse on the Y‐maze beginning at 10 months of age irrespective of diet.ConclusionAerobic capacity and diet affect brain health during aging. Liver function appears to play a large role in brain health outcomes. We continue to analyze MRI/MRS and cognitive data in correlation with liver function.