Exercise prevents fatty liver by modifying the compensatory response of mitochondrial metabolism to excess substrate availability

Abstract

Objective Liver 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. Methods We 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. Results HED 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. Conclusion We 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.

visMOP – A Visual Analytics Approach for Multi‐omics Pathways

“…In this example, one striking observation is that not only metabolites—i.e., lipids—but also transcripts and proteins are generally upregulated in pathways related to lipid metabolism. This includes several pathways concerned with the metabolism of fatty acids, in agreement with the original study [HKK*21] and indicates that the increased amount of fatty acids supplied with the fat‐rich diet in the study caused an increased utilization of these in the abovementioned pathways. In contrast, individual proteins and transcripts assigned to the fatty acyl‐CoA biosynthesis pathway, i.e., a pathway concerned with the synthesis of fatty acids, showed a higher degree of downregulation.…”

“…This concludes the exemplary workflow on how a hypothesis can be generated using visMOP, which can then later be confirmed via different means. In this case we showed a tendency in the data which was previously analyzed in detail and published [HKK*21]. There are a multitude of different entry points for further detail analysis, e.g., other clusters focusing on other processes.…”

“…Below, we show the application of our prototypical implementation of visMOP on a real‐life experimental datasets from M. musculus (house mouse) by performing a basic workflow to generate new hypotheses. The data [HKK*21] were acquired in an experimental study investigating the effects of high caloric feeding on mitochondrial lipid metabolism in the context of fatty liver disease. Samples were taken from liver tissue, and transcriptomic analysis was performed on whole tissue.…”

The crucial role and mechanism of insulin resistance in metabolic disease

“…It was shown that treadmill training modulates the increase in mitochondrial substrate oxidation in liver and skeletal muscle induced by a high-energy diet in mice, disconnecting it from pyruvate and acetyl CoA-driven lipid synthesis. This may help prevent the long-term deleterious effects of excessive nutritional intake on liver mitochondrial function and insulin sensitivity, thereby preventing the development of metabolic diseases such as fatty liver and NAFLD ( 269 ). As described in the mechanism section, intermittent hypoxia leads to disturbances in the gut microbiota-circulating exosome pathway, disrupting adipocyte homeostasis and leading to metabolic dysfunction manifested as IR, whereas experiments have shown that such changes can be attenuated by physical activity, as regular non-strenuous activity will lead to substantial improvements in the gut microbiota-exosome pathway ( 270 ).…”

The mitochondrial multi-omic response to exercise training across tissues

“…Exercise is a powerful modulator of mitochondrial function and health in muscle 16 and liver 17 , an effect that is conserved across mouse, rat and human. Importantly, while concerted efforts have been made to understand the mitochondrial multi-omic response in one or two tissues 63,64 , this has not been undertaken at the scale or breadth of this work. We show that endurance exercise training activates a concerted mitochondrial response in multiple tissues, including the scarcely investigated colon and adrenal glands.…”