AUTHOR=Huang Wei , Ruan Weiqi , Huo Cuilan , Lin Yanyu , Wang Tian , Dai Xiangdi , Zhai Haonan , Ma Jiasheng , Zhang Jingyi , Lu Jin , Zhuang Jie TITLE=The effect of 12 weeks of combined training on hepatic fat content and metabolic flexibility of individuals with non-alcoholic fatty liver disease: Protocol of an open-label, single-center randomized control trial JOURNAL=Frontiers in Nutrition VOLUME=Volume 9 - 2022 YEAR=2023 URL=https://www.frontiersin.org/journals/nutrition/articles/10.3389/fnut.2022.1065188 DOI=10.3389/fnut.2022.1065188 ISSN=2296-861X ABSTRACT=Introduction: Metabolic flexibility (MetF) is the capacity of an organism to oxidate substrate according to substrate availability or demand. The mismatch of substrate availability and oxidation may cause ectopic fat accumulation in muscle and liver. The objectives of the study are to examine the effect of 12-weeks combined exercise on hepatic fat reduction, and investigate metabolites related to MetF before and after the high-fat diet between individuals with NAFLD and healthy control with active lifestyle. Methods: This study is an open-label, single-center trial randomized controlled clinical study plus a cross-sectional comparison between individuals with NAFLD and healthy control. Individuals with NAFLD are allocated into two groups receiving resistance training(RT) combined with high-intensity interval training(HIIT) or moderate-intensity continuous training(MICT). Anthropometric indicators, clinical blood markers about glucose, lipid metabolism, and hepatic fat content(HFC) are assessed before and after the intervention. The metabolomics will also be used to investigate the discrepant metabolites and mechanisms related to MetF. Discussion: Metabolic flexibility reflects the capacity of an organism switches the oxidation of the substrate flexibly, which is associated with ectopic fat accumulation. Our study aims to explore the discrepant metabolites related to MetF before and after a high-fat diet between individuals with NAFLD and healthy control. In addition, the study will also examine the effectiveness of RT combined with HIIT or MICT on hepatic fat reduction, and quantificationally analyze the metabolites related to MetF before and after the intervention. Our results will provide a perspective on fatty liver-associated metabolic inactivity. Trial registration ClinicalTrials.gov: ChiCTR2200055110; Registered 31 December 2021, http://www.chictr.org.cn/index.aspx