{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T05:31:56Z","timestamp":1785216716595,"version":"3.55.0"},"reference-count":52,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T00:00:00Z","timestamp":1651795200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Jiangxi Province Bureau of Foreign Experts and National Nature Science Foundation of China","award":["81572753, 31660332, 81460374, 31460304, and 81560299"],"award-info":[{"award-number":["81572753, 31660332, 81460374, 31460304, and 81560299"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obesity often concurs with nonalcoholic fatty liver disease (NAFLD), both of which are detrimental to human health. Thus far, exercise appears to be an effective treatment approach. However, its effects cannot last long and, moreover, it is difficult to achieve for many obese people. Thus, it is necessary to look into alternative remedies. The present study explored a noninvasive, easy, tolerable physical alternative. In our experiment, C57BL\/6 mice were fed with a high-fat diet (HFD) to induce overweight\/obesity and were exposed to 10% oxygen for one hour every day. We found that hypoxia exerted protective effects. First, it offset HFD-induced bodyweight gain and insulin resistance. Secondly, hypoxia reversed the HFD-induced enlargement of white and brown adipocytes and fatty liver, and protected liver function. Thirdly, HFD downregulated the expression of genes required for lipolysis and thermogenesis, such as UCP1, ADR3(beta3-adrenergic receptor), CPT1A, ATGL, PPAR\u03b1, and PGC1\u03b1, M2 macrophage markers arginase and CD206 in the liver, and UCP1 and PPAR\u03b3 in brown fat, while these molecules were upregulated by hypoxia. Furthermore, hypoxia induced the activation of AMPK, an energy sensing enzyme. Fourthly, our results showed that hypoxia increased serum levels of epinephrine. Indeed, the effects of hypoxia on bodyweight, fatty liver, and associated changes in gene expression ever tested were reproduced by injection of epinephrine and prevented by propranolol at varying degrees. Altogether, our data suggest that hypoxia triggers stress responses where epinephrine plays important roles. Therefore, our study sheds light on the hope to use hypoxia to treat the daunting disorders, obesity and NAFLD.<\/jats:p>","DOI":"10.3390\/ijms23095209","type":"journal-article","created":{"date-parts":[[2022,5,6]],"date-time":"2022-05-06T14:49:38Z","timestamp":1651848578000},"page":"5209","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["Chronic Intermittent Hypoxia Exposure Alternative to Exercise Alleviates High-Fat-Diet-Induced Obesity and Fatty Liver"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6838-5950","authenticated-orcid":false,"given":"Yunfei","family":"Luo","sequence":"first","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiongfeng","family":"Chen","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junrong","family":"Zou","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingjing","family":"Fan","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanjun","family":"Li","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8105-5289","authenticated-orcid":false,"given":"Zhijun","family":"Luo","sequence":"additional","affiliation":[{"name":"Jiangxi Provincial Key Laboratory of Tumor Pathogens and Molecular Pathology, Department of Pathophysiology, Schools of Basic Sciences, Nanchang University, Nanchang 330031, China"},{"name":"Queen Mary School, Nanchang University, Nanchang 330031, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,6]]},"reference":[{"key":"ref_1","first-page":"36","article-title":"Obesity: An Emerging Threat","volume":"29","author":"Hill","year":"2018","journal-title":"J. Natl. Black Nurses\u2019 Assoc."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"117","DOI":"10.1159\/000350627","article-title":"Obesity: The gateway to ill health\u2014An EASO position statement on a rising public health, clinical and scientific challenge in Europe","volume":"6","author":"Toplak","year":"2013","journal-title":"Obes. Facts"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1016\/j.metabol.2018.11.014","article-title":"Obesity and nonalcoholic fatty liver disease: From pathophysiology to therapeutics","volume":"92","author":"Polyzos","year":"2019","journal-title":"Metabolism"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1191\/1740774504cn053oa","article-title":"The effects of an open design on trial participant recruitment, compliance and retention--a randomized controlled trial comparison with a blinded, placebo-controlled design","volume":"1","author":"Avenell","year":"2004","journal-title":"Clin. Trials"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1001\/jama.293.1.43","article-title":"Comparison of the Atkins, Ornish, Weight Watchers, and Zone diets for weight loss and heart disease risk reduction: A randomized trial","volume":"293","author":"Dansinger","year":"2005","journal-title":"JAMA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1210\/er.2014-1063","article-title":"Glucose homeostasis during short-term and prolonged exposure to high altitudes","volume":"36","author":"Woolcott","year":"2015","journal-title":"Endocr. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2631713","DOI":"10.1155\/2019\/2631713","article-title":"Correlates of Overweight in Children and Adolescents Living at Different Altitudes: The Peruvian Health and Optimist Growth Study","volume":"2019","author":"Santos","year":"2019","journal-title":"J. Obes."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"6353","DOI":"10.1080\/21655979.2021.2024950","article-title":"Research progress on the mechanism of cerebral blood flow regulation in hypoxia environment at plateau","volume":"13","author":"Hao","year":"2022","journal-title":"Bioengineered"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wang, Y., Shi, Y., Li, W., Wang, S., Zheng, J., Xu, G., Li, G., Shen, X., and Yang, J.A.-O. (FEBS J., 2022). Gut microbiota imbalance mediates intestinal barrier damage in high-altitude exposed mice, FEBS J., early view.","DOI":"10.1111\/febs.16409"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Xu, Z., You, W., Zhou, Y., Chen, W., Wang, Y., and Shan, T. (2019). Cold-induced lipid dynamics and transcriptional programs in white adipose tissue. BMC Biol., 17.","DOI":"10.1186\/s12915-019-0693-x"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1000","DOI":"10.1016\/j.ejvs.2019.10.014","article-title":"Intermittent Hypoxia Alleviates beta-Aminopropionitrile Monofumarate Induced Thoracic Aortic Dissection in C57BL\/6 Mice","volume":"59","author":"Yang","year":"2020","journal-title":"Eur. J. Vasc. Endovasc. Surg."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1136\/bmj.317.7165.1063","article-title":"ABC of oxygen: Oxygen at high altitude","volume":"317","author":"Peacock","year":"1998","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1097\/MEG.0000000000001235","article-title":"Nonalcoholic fatty liver disease: Current concepts, epidemiology and management strategies","volume":"30","author":"Tomic","year":"2018","journal-title":"Eur. J. Gastroenterol. Hepatol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"675","DOI":"10.1038\/oby.2009.509","article-title":"Hypobaric hypoxia causes body weight reduction in obese subjects","volume":"18","author":"Lippl","year":"2010","journal-title":"Obesity"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1089\/15270290260131939","article-title":"Intermittent hypoxia research in the former soviet union and the commonwealth of independent States: History and review of the concept and selected applications","volume":"3","author":"Serebrovskaya","year":"2002","journal-title":"High Alt. Med. Biol."},{"key":"ref_16","first-page":"48","article-title":"Efficiency of intermittent and resonance intermittent normobaric hypoxia therapy in patients with infection-dependent bronchial asthma","volume":"9","author":"AIa","year":"2000","journal-title":"Vestn. Ross. Akad. Meditsinskikh Nauk."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"88","DOI":"10.2174\/1573403X17666210514005235","article-title":"Safety and Efficacy of Intermittent Hypoxia Conditioning as a New Rehabilitation\/Secondary Prevention Strategy for Patients with Cardiovascular Diseases: A Systematic Review and Meta-analysis","volume":"17","author":"Glazachev","year":"2021","journal-title":"Curr. Cardiol. Rev."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1089\/ham.2019.0053","article-title":"Intermittent Hypoxia\/Hyperoxia Versus Intermittent Hypoxia\/Normoxia: Comparative Study in Prediabetes","volume":"20","author":"Serebrovska","year":"2019","journal-title":"High Alt. Med. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1159\/000029224","article-title":"Hypoxic ventilatory responses and gas exchange in patients with Parkinson\u2019s disease","volume":"65","author":"Serebrovskaya","year":"1998","journal-title":"Respiration"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"627","DOI":"10.3181\/0710-MR-267","article-title":"Intermittent hypoxia: Cause of or therapy for systemic hypertension?","volume":"233","author":"Serebrovskaya","year":"2008","journal-title":"Exp. Biol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.metabol.2009.07.014","article-title":"Acute altitude-induced hypoxia suppresses plasma glucose and leptin in healthy humans","volume":"59","author":"Kelly","year":"2010","journal-title":"Metabolism"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"869","DOI":"10.3923\/pjbs.2008.869.875","article-title":"The effect of intermittent hypoxia on bodyweight, serum glucose and cholesterol in obesity mice","volume":"11","author":"Ling","year":"2008","journal-title":"Pak. J. Biol. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1538","DOI":"10.1152\/japplphysiol.91523.2008","article-title":"Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers","volume":"106","author":"Louis","year":"2009","journal-title":"J. Appl. Physiol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"94","DOI":"10.1002\/dmrr.1156","article-title":"Acute hypoxia and exercise improve insulin sensitivity (S(I) (2*)) in individuals with type 2 diabetes","volume":"27","author":"Mackenzie","year":"2011","journal-title":"Diabetes\/Metab. Res. Rev."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1007\/BF02254369","article-title":"Effect of prolonged intermittent hypoxia and exercise training on glucose tolerance and muscle GLUT4 protein expression in rats","volume":"11","author":"Chiu","year":"2004","journal-title":"J. Biomed. Sci"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1016\/j.apmr.2011.08.046","article-title":"Exercise significantly increases plasma adrenaline and oxidized low-density lipoprotein in normal healthy subjects but not in persons with spinal cord injury","volume":"93","author":"Mitsui","year":"2012","journal-title":"Arch. Phys. Med. Rehabil."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1519\/JSC.0b013e318181fdfd","article-title":"The immunological and metabolic responses to exercise of varying intensities in normoxic and hypoxic environments","volume":"22","author":"Blegen","year":"2008","journal-title":"J. Strength Cond. Res."},{"key":"ref_28","first-page":"R197","article-title":"Hormonal response to exercise in humans: Influence of hypoxia and physical training","volume":"254","author":"Kjaer","year":"1988","journal-title":"Am. J. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"G811","DOI":"10.1152\/ajpgi.00047.2019","article-title":"Intermittent restraint-induced sympathetic activation attenuates hepatic steatosis and inflammation in a high-fat diet-fed mouse model","volume":"317","author":"Lee","year":"2019","journal-title":"Am. J. Physiol.-Gastrointest. Liver Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1016\/j.cellsig.2015.12.012","article-title":"Parathyroid hormone induces adipocyte lipolysis via PKA-mediated phosphorylation of hormone-sensitive lipase","volume":"28","author":"Larsson","year":"2016","journal-title":"Cell. Signal."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Xu, H.Y., Yu, L., Chen, J.H., Yang, L.N., Lin, C., Shi, X.Q., and Qin, H. (2020). Sesamol Alleviates Obesity-Related Hepatic Steatosis via Activating Hepatic PKA Pathway. Nutrients, 12.","DOI":"10.3390\/nu12020329"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1038\/nrm.2017.95","article-title":"AMPK: Guardian of metabolism and mitochondrial homeostasis","volume":"19","author":"Herzig","year":"2018","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"30272","DOI":"10.1038\/srep30272","article-title":"Sestrin2 Silencing Exacerbates Cerebral Ischemia\/Reperfusion Injury by Decreasing Mitochondrial Biogenesis through the AMPK\/PGC-1\u03b1 Pathway in Rats","volume":"6","author":"Li","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"342","DOI":"10.1007\/s13340-016-0290-y","article-title":"M2 macrophages in metabolism","volume":"7","author":"Fujisaka","year":"2016","journal-title":"Diabetol. Int."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"192","DOI":"10.1016\/j.celrep.2018.12.036","article-title":"Genetic Liver-Specific AMPK Activation Protects against Diet-Induced Obesity and NAFLD","volume":"26","author":"Garcia","year":"2019","journal-title":"Cell Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"110566","DOI":"10.1016\/j.celrep.2022.110566","article-title":"Selenoprotein P-mediated reductive stress impairs cold-induced thermogenesis in brown fat","volume":"38","author":"Oo","year":"2022","journal-title":"Cell Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"322","DOI":"10.2337\/diabetes.54.2.322","article-title":"Dissipating excess energy stored in the liver is a potential treatment strategy for diabetes associated with obesity","volume":"54","author":"Ishigaki","year":"2005","journal-title":"Diabetes"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"165762","DOI":"10.1016\/j.bbadis.2020.165762","article-title":"Lack of UCP1 stimulates fatty liver but mediates UCP1-independent action of beige fat to improve hyperlipidemia in Apoe knockout mice","volume":"1866","author":"Kataoka","year":"2020","journal-title":"Biochim. Biophys. Acta BBA\u2014Mol. Basis Dis."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1016\/j.cmet.2016.08.010","article-title":"AMPK\/\u03b1-Ketoglutarate Axis Dynamically Mediates DNA Demethylation in the Prdm16 Promoter and Brown Adipogenesis","volume":"24","author":"Yang","year":"2016","journal-title":"Cell Metab."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/s42255-019-0036-9","article-title":"AMPK activation protects against diet induced obesity through Ucp1-independent thermogenesis in subcutaneous white adipose tissue","volume":"1","author":"Pollard","year":"2019","journal-title":"Nat. Metab."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1097\/MOL.0b013e3282f9b54d","article-title":"Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism","volume":"19","author":"Flowers","year":"2008","journal-title":"Curr. Opin. Lipidol."},{"key":"ref_42","first-page":"S43","article-title":"Adrenaline: A physiological metabolic regulatory hormone in humans?","volume":"17","author":"Cryer","year":"1993","journal-title":"Int. J. Obes. Relat. Metab. Disord. J. Int. Assoc. Study Obes."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1600","DOI":"10.1249\/mss.0b013e3180de49d3","article-title":"Nonhematological mechanisms of improved sea-level performance after hypoxic exposure","volume":"39","author":"Gore","year":"2007","journal-title":"Med. Sci. Sports Exerc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1152\/jappl.2001.91.1.173","article-title":"Molecular adaptations in human skeletal muscle to endurance training under simulated hypoxic conditions","volume":"91","author":"Vogt","year":"2001","journal-title":"J. Appl. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"3133","DOI":"10.1242\/jeb.204.18.3133","article-title":"Muscle tissue adaptations to hypoxia","volume":"204","author":"Hoppeler","year":"2001","journal-title":"J. Exp. Biol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1165\/rcmb.2020-0492OC","article-title":"Hepatocyte HIF-1 and Intermittent Hypoxia Independently Impact Liver Fibrosis in Murine Nonalcoholic Fatty Liver Disease","volume":"65","author":"Mesarwi","year":"2021","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.bcp.2006.03.021","article-title":"Critical roles of AMP-activated protein kinase in the carcinogenic metal-induced expression of VEGF and HIF-1 proteins in DU145 prostate carcinoma","volume":"72","author":"Lee","year":"2006","journal-title":"Biochem. Pharmacol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1197","DOI":"10.1016\/j.bbrc.2006.02.088","article-title":"AMPK activation inhibits the expression of HIF-1alpha induced by insulin and IGF-1","volume":"342","author":"Treins","year":"2006","journal-title":"Biochemical Biophys. Res. Commun."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"799","DOI":"10.3389\/fphys.2018.00799","article-title":"Long-Term Chronic Intermittent Hypobaric Hypoxia Induces Glucose Transporter (GLUT4) Translocation Through AMP-Activated Protein Kinase (AMPK) in the Soleus Muscle in Lean Rats","volume":"9","author":"Siques","year":"2018","journal-title":"Front. Physiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"62","DOI":"10.4077\/CJP.2010.AMK078","article-title":"Effect of mild intermittent hypoxia on glucose tolerance, muscle morphology and AMPK-PGC-1alpha signaling","volume":"53","author":"Chen","year":"2010","journal-title":"Chin. J. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"11944","DOI":"10.1074\/jbc.RA119.008778","article-title":"Liver-specific deletion of IGF2 mRNA binding protein-2\/IMP2 reduces hepatic fatty acid oxidation and increases hepatic triglyceride accumulation","volume":"294","author":"Minichiello","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2806","DOI":"10.1111\/jcmm.16308","article-title":"AMPK inhibits Smad3-mediated autoinduction of TGF-\u03b21 in gastric cancer cells","volume":"25","author":"Zou","year":"2021","journal-title":"J. Cell. Mol. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5209\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:07:15Z","timestamp":1760137635000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5209"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,6]]},"references-count":52,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23095209"],"URL":"https:\/\/doi.org\/10.3390\/ijms23095209","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,6]]}}}