{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T14:06:37Z","timestamp":1771509997785,"version":"3.50.1"},"reference-count":38,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T00:00:00Z","timestamp":1655856000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Library of Medicine of the National Institutes of Health","award":["R01LM012854"],"award-info":[{"award-number":["R01LM012854"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Clocks &amp; Sleep"],"abstract":"<jats:p>Adipokines are a growing group of secreted proteins that play important roles in obesity, sleep disturbance, and metabolic derangements. Due to the complex interplay between adipokines, sleep, and metabolic regulation, an integrated approach is required to better understand the significance of adipokines in these processes. In the present study, we created and analyzed a network of six adipokines and their molecular partners involved in sleep disturbance and metabolic dysregulation. This network represents information flow from regulatory factors, adipokines, and physiologic pathways to disease processes in metabolic dysfunction. Analyses using network metrics revealed that obesity and obstructive sleep apnea were major drivers for the sleep associated metabolic dysregulation. Two adipokines, leptin and adiponectin, were found to have higher degrees than other adipokines, indicating their central roles in the network. These adipokines signal through major metabolic pathways such as insulin signaling, inflammation, food intake, and energy expenditure, and exert their functions in cardiovascular, reproductive, and autoimmune diseases. Leptin, AMP activated protein kinase (AMPK), and fatty acid oxidation were found to have global influence in the network and represent potentially important interventional targets for metabolic and sleep disorders. These findings underscore the great potential of using network based approaches to identify new insights and pharmaceutical targets in metabolic and sleep disorders.<\/jats:p>","DOI":"10.3390\/clockssleep4030027","type":"journal-article","created":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T21:31:06Z","timestamp":1655933466000},"page":"321-331","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Adipokines in Sleep Disturbance and Metabolic Dysfunction: Insights from Network Analysis"],"prefix":"10.3390","volume":"4","author":[{"given":"Zhikui","family":"Wei","sequence":"first","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8232-8840","authenticated-orcid":false,"given":"You","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raghu P.","family":"Upender","sequence":"additional","affiliation":[{"name":"Department of Neurology, Vanderbilt University Medical Center, Nashville, TN 37232, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"211","DOI":"10.1016\/j.smrv.2018.08.009","article-title":"Obstructive sleep apnea and the metabolic syndrome: The road to clinically-meaningful phenotyping, improved prognosis, and personalized treatment","volume":"42","author":"Gaines","year":"2018","journal-title":"Sleep Med. Rev."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.metabol.2018.04.001","article-title":"Association of sleep disturbances with obesity, insulin resistance and the metabolic syndrome","volume":"84","author":"Koren","year":"2018","journal-title":"Metabolism"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1183\/09059180.00003413","article-title":"Sleep apnoea and metabolic dysfunction","volume":"22","author":"Bonsignore","year":"2013","journal-title":"Eur. Respir. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.smrv.2014.07.004","article-title":"Impact of obstructive sleep apnea treatment by continuous positive airway pressure on cardiometabolic biomarkers: A systematic review from sham CPAP randomized controlled trials","volume":"21","author":"Tamisier","year":"2015","journal-title":"Sleep Med. Rev."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1210\/jcem.85.3.6484","article-title":"Sleep apnea and daytime sleepiness and fatigue: Relation to visceral obesity, insulin resistance, and hypercytokinemia","volume":"85","author":"Vgontzas","year":"2000","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"601","DOI":"10.1183\/09031936.00183411","article-title":"Sleep apnoea and visceral adiposity in middle-aged male and female subjects","volume":"41","author":"Kritikou","year":"2013","journal-title":"Eur. Respir. J."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1002\/prca.201100052","article-title":"Adipokines: A treasure trove for the discovery of biomarkers for metabolic disorders","volume":"6","author":"Lehr","year":"2012","journal-title":"Proteomics Clin. Appl."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1648","DOI":"10.1194\/jlr.R094060","article-title":"Beyond adiponectin and leptin: Adipose tissue-derived mediators of inter-organ communication","volume":"60","author":"Funcke","year":"2019","journal-title":"J. Lipid Res."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wei, Z., Chen, Y., and Upender, R.P. (2022). Sleep Disturbance and Metabolic Dysfunction: The Roles of Adipokines. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23031706"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"34","DOI":"10.3389\/fbioe.2020.00034","article-title":"A Guide to Conquer the Biological Network Era Using Graph Theory","volume":"8","author":"Koutrouli","year":"2020","journal-title":"Front. Bioeng. Biotechnol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1093\/scan\/nsaa069","article-title":"Social Network Analysis for Social Neuroscientists","volume":"16","author":"Baek","year":"2021","journal-title":"Soc. Cogn. Affect. Neurosci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1146\/annurev-biodatasci-080917-013444","article-title":"Network Analysis as a Grand Unifier in Biomedical Data Science","volume":"1","author":"McGillivray","year":"2018","journal-title":"Annu. Rev. Biomed. Data Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1785","DOI":"10.1016\/j.jacc.2016.06.072","article-title":"The Adipokine-Cardiovascular-Lifestyle Network: Translation to Clinical Practice","volume":"68","author":"Mechanick","year":"2016","journal-title":"J. Am. Coll. Cardiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Yu, H., Kim, P.M., Sprecher, E., Trifonov, V., and Gerstein, M. (2007). The importance of bottlenecks in protein networks: Correlation with gene essentiality and expression dynamics. PLoS Comput. Biol., 3.","DOI":"10.1371\/journal.pcbi.0030059"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1089\/cmb.2008.04TT","article-title":"Bottlenecks and hubs in inferred networks are important for virulence in Salmonella typhimurium","volume":"16","author":"McDermott","year":"2009","journal-title":"J. Comput. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1093\/jmcb\/mjw011","article-title":"Adiponectin, the past two decades","volume":"8","author":"Wang","year":"2016","journal-title":"J. Mol. Cell Biol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1016\/j.metabol.2014.08.004","article-title":"Physiology of leptin: Energy homeostasis, neuroendocrine function and metabolism","volume":"64","author":"Park","year":"2015","journal-title":"Metabolism"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.tcm.2010.12.002","article-title":"Omentin: A novel link between inflammation, diabesity, and cardiovascular disease","volume":"20","author":"Tan","year":"2010","journal-title":"Trends Cardiovasc. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1007\/5584_2018_241","article-title":"Molecular Mechanisms of Vaspin Action\u2014From Adipose Tissue to Skin and Bone, from Blood Vessels to the Brain","volume":"1111","author":"Weiner","year":"2019","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/1758-5996-2-21","article-title":"Visfatin, glucose metabolism and vascular disease: A review of evidence","volume":"2","author":"Oliveira","year":"2010","journal-title":"Diabetol. Metab. Syndr."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"R79","DOI":"10.1530\/JOE-18-0174","article-title":"Chemerin: A multifaceted adipokine involved in metabolic disorders","volume":"238","author":"Helfer","year":"2018","journal-title":"J. Endocrinol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Bastian, M., Heymann, S., and Jacomy, M. (2009, January 17\u201320). Gephi: An open source software for exploring and manipulating networks. Proceedings of the Third International AAAI Conference on Weblogs and Social Media, San Jose, CA, USA.","DOI":"10.1609\/icwsm.v3i1.13937"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1007\/s11886-017-0916-0","article-title":"Sleep and Cardio-Metabolic Disease","volume":"19","author":"Cappuccio","year":"2017","journal-title":"Curr. Cardiol. Rep."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1038\/s41366-019-0405-1","article-title":"Childhood sleep duration modifies the polygenic risk for obesity in youth through leptin pathway: The Beijing Child and Adolescent Metabolic Syndrome cohort study","volume":"43","author":"Fu","year":"2019","journal-title":"Int. J. Obes."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1042\/CS20080066","article-title":"AMP-activated protein kinase pathway: A potential therapeutic target in cardiometabolic disease","volume":"116","author":"Wong","year":"2009","journal-title":"Clin. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Martins, F.O., Sacramento, J.F., Olea, E., Melo, B.F., Prieto-Lloret, J., Obeso, A., Rocher, A., Matafome, P., Monteiro, E.C., and Conde, S.V. (2021). Chronic Intermittent Hypoxia Induces Early-Stage Metabolic Dysfunction Independently of Adipose Tissue Deregulation. Antioxidants, 10.","DOI":"10.3390\/antiox10081233"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"16160","DOI":"10.1038\/srep16160","article-title":"Habitual Sleep Duration and Risk of Childhood Obesity: Systematic Review and Dose-response Meta-analysis of Prospective Cohort Studies","volume":"5","author":"Ruan","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"66","DOI":"10.4239\/wjd.v9.i4.66","article-title":"Correlation between metabolic syndrome and sleep apnea","volume":"9","author":"Castaneda","year":"2018","journal-title":"World J. Diabetes"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"485","DOI":"10.1507\/endocrj.EJ20-0036","article-title":"Effects of different obesity-related adipokines on the occurrence of obstructive sleep apnea","volume":"67","author":"Xu","year":"2020","journal-title":"Endocr. J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.5665\/sleep.5762","article-title":"Localizing Effects of Leptin on Upper Airway and Respiratory Control during Sleep","volume":"39","author":"Yao","year":"2016","journal-title":"Sleep"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"716","DOI":"10.1152\/jappl.1996.81.2.716","article-title":"Modified control of breathing in genetically obese (ob\/ob) mice","volume":"81","author":"Tankersley","year":"1996","journal-title":"J. Appl. Physiol. (1985)"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"R894","DOI":"10.1152\/ajpregu.00304.2005","article-title":"Altered sleep regulation in leptin-deficient mice","volume":"290","author":"Laposky","year":"2006","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1038\/nrg2918","article-title":"Network medicine: A network-based approach to human disease","volume":"12","author":"Gulbahce","year":"2011","journal-title":"Nat. Rev. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1002\/jcb.24457","article-title":"Target network analysis of adiponectin, a multifaceted adipokine","volume":"114","author":"Chen","year":"2013","journal-title":"J. Cell Biochem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"281","DOI":"10.2337\/db18-0892","article-title":"A Network Analysis of Biomarkers for Type 2 Diabetes","volume":"68","author":"Huang","year":"2019","journal-title":"Diabetes"},{"key":"ref_36","first-page":"959","article-title":"Investigation into the underlying molecular mechanisms of white adipose tissue through comparative transcriptome analysis of multiple tissues","volume":"19","author":"Zhang","year":"2019","journal-title":"Mol. Med. Rep."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"pe11","DOI":"10.1126\/scisignal.260pe11","article-title":"How perfect can protein interactomes be?","volume":"2","author":"Levy","year":"2009","journal-title":"Sci. Signal."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1016\/S0083-6729(05)71012-8","article-title":"Leptin: Structure, function and biology","volume":"71","author":"Zhang","year":"2005","journal-title":"Vitam. Horm."}],"container-title":["Clocks &amp; Sleep"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2624-5175\/4\/3\/27\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:37:41Z","timestamp":1760139461000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2624-5175\/4\/3\/27"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,22]]},"references-count":38,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,9]]}},"alternative-id":["clockssleep4030027"],"URL":"https:\/\/doi.org\/10.3390\/clockssleep4030027","relation":{},"ISSN":["2624-5175"],"issn-type":[{"value":"2624-5175","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,22]]}}}