Exercise prevents fatty liver by modifying the compensatory response of mitochondrial metabolism to excess substrate availability
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PROVIDER: PRJNA702786 | ENA |
REPOSITORIES: ENA
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Project description:Exercise training is a potent treatment of NAFLD and hepatic insulin resistance. Here we provide molecular information about the hepatic mitochondrial metabolism in mice when chronic overnutrition (high-energy diet (HED) for 6 weeks) is combined with exercise training. Training reduced the hepatic triacylglycerol content, fasting insulin, and reversed glucose intolerance. Training modified the hepatic mitochondrial proteome with a decrease in enzymes related to pyruvate metabolism and entry of acetyl-CoA into the TCA cycle. Transcriptome data revealed down-regulation of glucose oxidation and lipogenesis. The mitochondrial respiratory capacity of trained HED-fed mice is increased despite reduced content of complex I. Training decreased diacylglycerol species and JNK phosphorylation, both of which can induce insulin resistance. Increased mitochondrial mass and oxidative capacity of the trained muscle further unburdens the liver from substrate overload. Together, when high fat and carbohydrate intake in mice is accompanied by exercise, the decline of mitochondrial function and insulin resistance can be prevented by modification of mitochondrial acetyl-CoA metabolism.
2021-10-15 | GSE167046 | GEO
Project description:ObjectiveLiver mitochondria adapt to high-calorie intake. We investigated how exercise alters the early compensatory response of mitochondria, thus preventing fatty liver disease as a long-term consequence of overnutrition.MethodsWe compared the effects of a steatogenic high-energy diet (HED) for six weeks on mitochondrial metabolism of sedentary and treadmill-trained C57BL/6N mice. We applied multi-OMICs analyses to study the alterations in the proteome, transcriptome, and lipids in isolated mitochondria of liver and skeletal muscle as well as in whole tissue and examined the functional consequences by high-resolution respirometry.ResultsHED increased the respiratory capacity of isolated liver mitochondria, both in sedentary and in trained mice. However, proteomics analysis of the mitochondria and transcriptomics indicated that training modified the adaptation of the hepatic metabolism to HED on the level of respiratory complex I, glucose oxidation, pyruvate and acetyl-CoA metabolism, and lipogenesis. Training also counteracted the HED-induced glucose intolerance, the increase in fasting insulin, and in liver fat by lowering diacylglycerol species and c-Jun N-terminal kinase (JNK) phosphorylation in the livers of trained HED-fed mice, two mechanisms that can reverse hepatic insulin resistance. In skeletal muscle, the combination of HED and training improved the oxidative capacity to a greater extent than training alone by increasing respiration of isolated mitochondria and total mitochondrial protein content.ConclusionWe provide a comprehensive insight into the early adaptations of mitochondria in the liver and skeletal muscle to HED and endurance training. Our results suggest that exercise disconnects the HED-induced increase in mitochondrial substrate oxidation from pyruvate and acetyl-CoA-driven lipid synthesis. This could contribute to the prevention of deleterious long-term effects of high fat and sugar intake on hepatic mitochondrial function and insulin sensitivity.
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Project description:Barophilic growth of the hyperthermophilic methanarchaeon Methanocaldococcus jannaschii occurred when gas-substrate availability did not limit growth. In contrast, when growth was limited by gas transfer, no enhancement of growth was evident and a stress response was exhibited at both high and low pressure. A pressure-induced transcriptional response was evident, regardless of whether growth was enhanced by pressure. High-pressure adaptation of a barophilic organism can thus occur at the transcriptional level, even though the cells are stressed by low substrate availability and do not exhibit accelerated growth. Keywords: stress response, gas substrate limitation, bioreactor volume, high pressure
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