Heat Treatment Improves Hepatic Mitochondrial Respiratory Efficiency via Mitochondrial Remodeling

Abstract

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.

Heat Therapy Can Improve Hepatic Mitochondrial Function and Glucose Control

“…Supporting the role of HSP72 in mediating these effects, we have also shown that increased insulin-stimulated glucose uptake in response to heat treatment only occurs in the presence of normal HSP72 levels in siRNAtreated glycolytic muscles of rats bred for low-capacity running (36). We came to the same conclusion in a liver-specific HSP72 KO mouse model, demonstrating that the normal improvements in glucose control with heat treatment are eliminated in the absence of hepatic HSP72 (37).…”

“…3I). Repeated bouts of heat therapy (nine sessions at 42°C every 72 h for 4 wk) improve mitochondrial respiration, reduce mitochondrial H 2 O 2 emission, and increase proteins involved in mitochondrial transport, mitochondrial organization, and protein folding (37) (representative data in Figs. 3E-H).…”

“…Qualitative visual confirmation of mitophagy was obtained via confocal imaging of livers from WT animals exposed to the Ad-Cox8-GFP-mCherry fluorescent mitophagy reporter at 0 h after sham or HT time points (J). (Reprinted from Von Schulze et al(37). (CC BY 4.0)).…”

Heating Up to Heal—Acute Heat Exposure Increases Hepatic Mitophagy Resulting in Hormetic Improvements in Mitochondrial Bioenergetic Efficiency

“…In the latest issue of Function , Von Schulze et al 1 elegantly combine metabolic physiology with sophisticated bioenergetic analyses to elucidate the acute and chronic impacts of heat treatment (HT) across the hepatic mitochondrial network. This work is based on a collection of evidence, from this group and others, suggesting that impairments in mitochondrial functionality and/or quality control may underly non-alcoholic fatty liver disease (NAFLD).…”

“…From a therapeutic perspective, the results of Von Schulze et al 1 have far-reaching implications, particularly with respect to individuals suffering from NAFLD for which exercise interventions are contraindicated. With respect to hepatic mitochondrial biology, one of the most interesting findings of this work centers upon the observation that chronic HT both improved intrinsic bioenergetic efficiency while simultaneously decreasing hepatic mitochondrial content.…”