Title: Exercise‐induced α‐ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1‐dependent adrenal activation
Abstract: Article27 February 2020Open Access Source DataTransparent process Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation Yexian Yuan Yexian Yuan Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Pingwen Xu Pingwen Xu Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA Search for more papers by this author Qingyan Jiang Qingyan Jiang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Xingcai Cai Xingcai Cai Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Tao Wang Tao Wang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Wentong Peng Wentong Peng Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Jiajie Sun Jiajie Sun Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Canjun Zhu Canjun Zhu Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Cha Zhang Cha Zhang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Dong Yue Dong Yue Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Zhihui He Zhihui He Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Jinping Yang Jinping Yang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Yuxian Zeng Yuxian Zeng Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Man Du Man Du Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Fenglin Zhang Fenglin Zhang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Lucas Ibrahimi Lucas Ibrahimi Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA Search for more papers by this author Sarah Schaul Sarah Schaul Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA Search for more papers by this author Yuwei Jiang Yuwei Jiang Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL, USA Search for more papers by this author Jiqiu Wang Jiqiu Wang Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Jia Sun Jia Sun Zhujiang Hospital, Southern Medical University, Guangzhou, China Search for more papers by this author Qiaoping Wang Qiaoping Wang School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University Guangzhou, Guangzhou, China Search for more papers by this author Liming Liu Liming Liu State Key Laboratory of Food Science and Technology and Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi, China Search for more papers by this author Songbo Wang Songbo Wang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Lina Wang Lina Wang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Xiaotong Zhu Xiaotong Zhu Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Ping Gao Ping Gao Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Qianyun Xi Qianyun Xi Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Cong Yin Cong Yin Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Fan Li Fan Li Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Guli Xu Guli Xu Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Yongliang Zhang Yongliang Zhang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Gang Shu Corresponding Author Gang Shu [email protected] orcid.org/0000-0002-1321-4396 Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, ChinaLead author Search for more papers by this author Yexian Yuan Yexian Yuan Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Pingwen Xu Pingwen Xu Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA Search for more papers by this author Qingyan Jiang Qingyan Jiang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Xingcai Cai Xingcai Cai Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Tao Wang Tao Wang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Wentong Peng Wentong Peng Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Jiajie Sun Jiajie Sun Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Canjun Zhu Canjun Zhu Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Cha Zhang Cha Zhang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Dong Yue Dong Yue Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Zhihui He Zhihui He Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Jinping Yang Jinping Yang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Yuxian Zeng Yuxian Zeng Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Man Du Man Du Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Fenglin Zhang Fenglin Zhang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Lucas Ibrahimi Lucas Ibrahimi Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA Search for more papers by this author Sarah Schaul Sarah Schaul Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA Search for more papers by this author Yuwei Jiang Yuwei Jiang Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL, USA Search for more papers by this author Jiqiu Wang Jiqiu Wang Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China Search for more papers by this author Jia Sun Jia Sun Zhujiang Hospital, Southern Medical University, Guangzhou, China Search for more papers by this author Qiaoping Wang Qiaoping Wang School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University Guangzhou, Guangzhou, China Search for more papers by this author Liming Liu Liming Liu State Key Laboratory of Food Science and Technology and Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi, China Search for more papers by this author Songbo Wang Songbo Wang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Lina Wang Lina Wang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Xiaotong Zhu Xiaotong Zhu Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Ping Gao Ping Gao Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Qianyun Xi Qianyun Xi Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Cong Yin Cong Yin Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Fan Li Fan Li Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Guli Xu Guli Xu Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Yongliang Zhang Yongliang Zhang Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China Search for more papers by this author Gang Shu Corresponding Author Gang Shu [email protected] orcid.org/0000-0002-1321-4396 Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, ChinaLead author Search for more papers by this author Author Information Yexian Yuan1,‡, Pingwen Xu2,‡, Qingyan Jiang1,‡, Xingcai Cai1, Tao Wang1, Wentong Peng1, Jiajie Sun1, Canjun Zhu1, Cha Zhang1, Dong Yue1, Zhihui He1, Jinping Yang1, Yuxian Zeng1, Man Du1, Fenglin Zhang1, Lucas Ibrahimi2, Sarah Schaul2, Yuwei Jiang3, Jiqiu Wang4, Jia Sun5, Qiaoping Wang6, Liming Liu7, Songbo Wang1, Lina Wang1, Xiaotong Zhu1, Ping Gao1, Qianyun Xi1, Cong Yin1, Fan Li1, Guli Xu1, Yongliang Zhang1 and Gang Shu *,1 1Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, China 2Division of Endocrinology, Department of Medicine, The University of Illinois at Chicago, Chicago, IL, USA 3Department of Physiology and Biophysics, The University of Illinois at Chicago, Chicago, IL, USA 4Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China 5Zhujiang Hospital, Southern Medical University, Guangzhou, China 6School of Pharmaceutical Sciences (Shenzhen), Sun Yat-Sen University Guangzhou, Guangzhou, China 7State Key Laboratory of Food Science and Technology and Key Laboratory of Industrial Biotechnology, Ministry of Education, Jiangnan University, Wuxi, China ‡These authors contributed equally to this work *Corresponding author. Tel: +86 20 85284901; Fax: +86 20 85284901; E-mail: [email protected] The EMBO Journal (2020)39:e103304https://doi.org/10.15252/embj.2019103304 Correction(s) for this article Exercise-induced α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation15 July 2021 Correction added on 15 July 2021, after first online publication: new source data have been provided for this figure; see the associated Corrigendum at https://doi.org/10.15252/embj.2021108434 Correction added on 15 July 2021, after first online publication: endurance was changed to resistance; see the associated Corrigendum at https://doi.org/10.15252/embj.2021108434 PDFDownload PDF of article text and main figures. Peer ReviewDownload a summary of the editorial decision process including editorial decision letters, reviewer comments and author responses to feedback. ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinked InMendeleyWechatReddit Figures & Info Abstract Beneficial effects of resistance exercise on metabolic health and particularly muscle hypertrophy and fat loss are well established, but the underlying chemical and physiological mechanisms are not fully understood. Here, we identified a myometabolite-mediated metabolic pathway that is essential for the beneficial metabolic effects of resistance exercise in mice. We showed that substantial accumulation of the tricarboxylic acid cycle intermediate α-ketoglutaric acid (AKG) is a metabolic signature of resistance exercise performance. Interestingly, human plasma AKG level is also negatively correlated with BMI. Pharmacological elevation of circulating AKG induces muscle hypertrophy, brown adipose tissue (BAT) thermogenesis, and white adipose tissue (WAT) lipolysis in vivo. We further found that AKG stimulates the adrenal release of adrenaline through 2-oxoglutarate receptor 1 (OXGR1) expressed in adrenal glands. Finally, by using both loss-of-function and gain-of-function mouse models, we showed that OXGR1 is essential for AKG-mediated exercise-induced beneficial metabolic effects. These findings reveal an unappreciated mechanism for the salutary effects of resistance exercise, using AKG as a systemically derived molecule for adrenal stimulation of muscle hypertrophy and fat loss. Synopsis The mechanisms underlying the beneficial effects of resistance exercise on body metabolism are poorly understood. Here, the Krebs cycle intermediate α-ketoglutaric acid (AKG) is identified as an exercise-induced, muscle-derived metabolite, enhancing muscle growth and lipolysis via systemic stimulation of the adrenal gland. Acute resistance exercise increases plasma AKG levels and muscular AKG synthesis. AKG induces muscle hypertrophy and fat loss in vivo in mouse obesity models. AKG activates the adrenal gland, enhancing enhanced thermogenesis and lipolysis. OXGR1 is required for AKG-mediated secretion of serum E. Introduction Obesity is recognized as a global epidemic, and there is an urgent need to control obesity and obesity-related metabolic diseases (Gungor, 2014). Among diverse promising strategies for preventing obesity, physical exercise is considered to be one of the most effective ways of controlling body weight. Numerous intervention studies have evaluated the role of exercise in the attainment and maintenance of healthy body weight, as well as additional beneficial effects on metabolic, respiratory, and cardiovascular function independent of weight loss (DiPietro & Stachenfeld, 2000; Strasser, 2013). However, exercise presents variations in duration and intensity that promote different mechanical and metabolic stimuli, which result in distinct beneficial effects on cardiovascular function, whole-body metabolism, and glucose homeostasis. Among the various classifications of exercise, endurance (aerobic) and resistance (nonaerobic) exercise are highlighted. Specifically, endurance exercise is a low-intensity and long-duration format of training, while resistance exercise is characterized by a high intensity and short duration (Patel et al, 2017). Endurance exercise is widely considered to increase endurance and cardiac health, while resistance exercise presents stimulatory effects on fat loss and muscle hypertrophy (Kilani, 2010). Although both endurance and resistance exercise lead to fat loss (Benito et al, 2015), resistance but not endurance exercise increases muscle mass and resting metabolic rate (Poehlman et al, 1991, 2002; Dolezal & Potteiger, 1998; Hunter et al, 2000), providing better weight loss maintenance in long-term observation. There have been numerous analyses of plasma metabolites following acute endurance exercise in both clinical and animal models (Lewis et al, 2010; Huffman et al, 2014; Aguer et al, 2017; Duft et al, 2017; Starnes et al, 2017; Sato et al, 2019), which has generated a number of metabolomics “signatures” in the circulation. These plasmas metabolic profiles provide signatures of endurance exercise performance and cardiovascular disease susceptibility and also identify molecular pathways that may modulate the salutary effects on cardiovascular function. However, very few metabolomics data are available for resistance exercise (Li et al, 2012; Berton et al, 2017), and the underlying chemical and physiological mechanisms for the stimulatory effects of resistance exercise on fat loss and muscle hypertrophy are not fully understood. Our goal is to identify the essential mediator for the beneficial metabolic effects of resistance exercise and provide potential therapeutic strategies to mimic the health effects of resistance exercise to combat obesity. Emerging evidence has identified skeletal muscle as a secretory organ in regulating energy homeostasis and obesity progression in other tissues (Rai & Demontis, 2016; Ibrahim et al, 2017). Exercise can induce systemic metabolic effects either via changes in the mass and metabolic demand of muscle or via the release of muscle-derived cytokines (myokines) and metabolites (myometabolites) to target different downstream tissues (Schnyder & Handschin, 2015). Many myokines secreted in response to exercise improve glucose homeostasis and protect against obesity, such as irisin (Bostrom et al, 2012), interleukin-15 (IL-15) (Barra et al, 2014), and Meteorin-like (METRNL) (Rao et al, 2014). Similarly, myometabolites can mediate exercise-induced metabolic functions. For example, β-aminoisobutyric acid (BAIBA), a novel exercise-induced muscle factor, attenuates insulin resistance, improves glucose tolerance, and promotes the browning of white adipose tissue (WAT) and hepatic β-oxidation (Roberts et al, 2014; Jung et al, 2015). In addition to their roles as metabolic substrates for gluconeogenesis, alanine and glutamine, the major amino acids released by skeletal muscle, can also act as hormone secretagogues and regulate the release of insulin, insulin-like growth factor 1, glucagon, and growth hormone (Nair & Short, 2005). Lactate, another prominent myometabolite released during exercise, has been proposed as a systemic modulator of metabolic homeostasis and the redox state (Brosnan & Letto, 1991; Corkey & Shirihai, 2012; Finsterer, 2012; Salgueiro et al, 2014). While metabolite therapies for obesity are emerging, metabolite-induced beneficial effects on improvement of obesity continue to face a serious challenge of low long-term therapeutic efficiency. Here, we aim to identify the essential exercise-induced myometabolites, which may mimic the long-term potent anti-obesity effects of regular physical exercise. In the present study, we first applied a comparative metabolomics approach and demonstrated that substantial accumulation of a tricarboxylic acid (TCA) cycle intermediate, α-ketoglutaric acid (AKG), is a serum metabolic signature of acute resistance exercise in mice. We also found human plasma AKG is negatively correlated with BMI. We then systematically characterized the metabolic effects of AKG treatment in mice fed on chow or high-fat diet (HFD). Further, we used both loss-of-function and gain-of-function mouse models to determine whether AKG receptor OXGR1, expressed by the adrenal glands, is required for the anti-obesity effects of AKG. Finally, we tested whether OXGR1 is essential for resistance exercise-induced metabolic beneficial effects. Collectively, these results support the notion that AKG is an essential mediator of resistance exercise-induced beneficial metabolic effects. Notably, these data suggest that pharmacologically targeting the AKG–OXGR1 pathway may mimic some of the benefits of resistance exercise to improve metabolic health in vivo. Results Exercise induces the enrichment of AKG Consistent with the previous observation that physical exercise can effectively decrease fat deposition (Maillard et al, 2018), we found that both ladder-climbing (resistance) and treadmill (endurance) exercise had similar effects of inhibiting HFD-induced body weight gain (Fig 1A). However, resistance exercise showed better beneficial metabolic effects compared with endurance exercise, as indicated by the higher lean mass and lower fat mass (Fig 1B) and gonadal adipose tissue (gWAT) index (Fig 1C). To search for the essential mediators of resistance exercise-induced metabolic salutary effects, we assessed the relative changes in serum metabolites in response to resistance exercise by using mass spectrometry to measure metabolites after resistance exercise in male mice. We obtained peripheral blood samples from both unexercised control mice and mice after acute resistance exercise (40 min at t