{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T12:54:21Z","timestamp":1788785661671,"version":"build-2803163510"},"reference-count":36,"publisher":"American Diabetes Association","issue":"9","license":[{"start":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T00:00:00Z","timestamp":1624838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.diabetesjournals.org\/content\/license"}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2021,9,1]]},"abstract":"<jats:p>Work in recent decades has established that metabolic hormones released by endocrine cells and diverse other cell types serve to regulate nutrient intake and energy homeostasis. Tsukushi (TSK) is a leucine-rich repeat-containing protein secreted primarily by the liver that exerts an inhibitory effect on brown fat sympathetic innervation and thermogenesis. Despite this, physiological regulation of TSK and the mechanisms underlying its effects on energy balance remain poorly understood. Here we show that hepatic expression and plasma concentrations of TSK are induced by feeding and regulated by melanocortin-4 receptor (MC4R) signaling. We generated TSK and MC4R\u2013double-knockout mice to elucidate the nature of cross talk between TSK and the central regulatory circuit of energy balance. Remarkably, TSK inactivation restores energy balance, ameliorates hyperphagia, and improves metabolic health in MC4R-deficient mice. TSK ablation enhances thermogenic gene expression in brown fat, dampens obesity-association inflammation in the liver and adipose tissue, and protects MC4R-null mice from diet-induced nonalcoholic steatohepatitis. At the cellular level, TSK deficiency augments feeding-induced c-Fos expression in the paraventricular nucleus of the hypothalamus. These results illustrate physiological cross talk between TSK and the central regulatory circuit in maintaining energy balance and metabolic homeostasis.<\/jats:p>","DOI":"10.2337\/db21-0161","type":"journal-article","created":{"date-parts":[[2021,6,28]],"date-time":"2021-06-28T12:25:27Z","timestamp":1624883127000},"page":"2081-2091","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":14,"title":["Deletion of the Feeding-Induced Hepatokine TSK Ameliorates the Melanocortin Obesity Syndrome"],"prefix":"10.2337","volume":"70","author":[{"given":"Qiuyu","family":"Wang","sequence":"first","affiliation":[{"name":"Life Sciences Institute and Department of Cell & Developmental Biology, Michigan Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Life Sciences Institute and Department of Cell & Developmental Biology, Michigan Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isin","family":"Cakir","sequence":"additional","affiliation":[{"name":"Life Sciences Institute and Department of Molecular & Integrated Physiology, Michigan Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Mi","sequence":"additional","affiliation":[{"name":"Life Sciences Institute and Department of Cell & Developmental Biology, Michigan Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger D.","family":"Cone","sequence":"additional","affiliation":[{"name":"Life Sciences Institute and Department of Molecular & Integrated Physiology, Michigan Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8069-5647","authenticated-orcid":false,"given":"Jiandie D.","family":"Lin","sequence":"additional","affiliation":[{"name":"Life Sciences Institute and Department of Cell & Developmental Biology, Michigan Medicine, University of Michigan, Ann Arbor, MI"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2021,6,28]]},"reference":[{"key":"2022031309253106400_B1","doi-asserted-by":"crossref","first-page":"1784","DOI":"10.1172\/JCI29126","article-title":"Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome","volume":"116","author":"Kadowaki","year":"2006","journal-title":"J Clin Invest"},{"key":"2022031309253106400_B2","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1210\/er.2006-0033","article-title":"Adipose tissue-derived factors: impact on health and disease","volume":"27","author":"Trujillo","year":"2006","journal-title":"Endocr Rev"},{"key":"2022031309253106400_B3","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1146\/annurev.pathol.2.010506.091859","article-title":"Endocrine functions of adipose tissue","volume":"2","author":"Waki","year":"2007","journal-title":"Annu Rev Pathol"},{"key":"2022031309253106400_B4","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1038\/nrendo.2017.56","article-title":"Hepatokines: linking nonalcoholic fatty liver disease and insulin resistance","volume":"13","author":"Meex","year":"2017","journal-title":"Nat Rev Endocrinol"},{"key":"2022031309253106400_B5","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1038\/nrendo.2012.258","article-title":"The role of hepatokines in metabolism","volume":"9","author":"Stefan","year":"2013","journal-title":"Nat Rev Endocrinol"},{"key":"2022031309253106400_B6","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1016\/j.cmet.2012.11.001","article-title":"Circulating fibroblast growth factors as metabolic regulators--a critical appraisal","volume":"16","author":"Angelin","year":"2012","journal-title":"Cell Metab"},{"key":"2022031309253106400_B7","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1101\/gad.184788.111","article-title":"Endocrine fibroblast growth factors 15\/19 and 21: from feast to famine","volume":"26","author":"Potthoff","year":"2012","journal-title":"Genes Dev"},{"key":"2022031309253106400_B8","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1038\/nrendo.2012.49","article-title":"Muscles, exercise and obesity: skeletal muscle as a secretory organ","volume":"8","author":"Pedersen","year":"2012","journal-title":"Nat Rev Endocrinol"},{"key":"2022031309253106400_B9","doi-asserted-by":"crossref","first-page":"T157","DOI":"10.1530\/JME-16-0014","article-title":"60 years of POMC: regulation of feeding and energy homeostasis by \u03b1-MSH","volume":"56","author":"Anderson","year":"2016","journal-title":"J Mol Endocrinol"},{"key":"2022031309253106400_B10","doi-asserted-by":"crossref","first-page":"206","DOI":"10.1038\/nn.4202","article-title":"Melanocortin-4 receptor-regulated energy homeostasis","volume":"19","author":"Krashes","year":"2016","journal-title":"Nat Neurosci"},{"key":"2022031309253106400_B11","doi-asserted-by":"crossref","first-page":"415","DOI":"10.1016\/j.cmet.2007.05.003","article-title":"Endocrine regulation of the fasting response by PPARalpha-mediated induction of fibroblast growth factor 21","volume":"5","author":"Inagaki","year":"2007","journal-title":"Cell Metab"},{"key":"2022031309253106400_B12","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.molmet.2016.11.008","article-title":"A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism","volume":"6","author":"Fisher","year":"2016","journal-title":"Mol Metab"},{"key":"2022031309253106400_B13","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1146\/annurev-physiol-021115-105339","article-title":"Understanding the physiology of FGF21","volume":"78","author":"Fisher","year":"2016","journal-title":"Annu Rev Physiol"},{"key":"2022031309253106400_B14","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.1038\/nm.3249","article-title":"FGF21 regulates metabolism and circadian behavior by acting on the nervous system","volume":"19","author":"Bookout","year":"2013","journal-title":"Nat Med"},{"key":"2022031309253106400_B15","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/s42255-018-0020-9","article-title":"The hepatokine Tsukushi gates energy expenditure via brown fat sympathetic innervation","volume":"1","author":"Wang","year":"2019","journal-title":"Nat Metab"},{"key":"2022031309253106400_B16","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.ydbio.2012.11.029","article-title":"The combinatorial guidance activities of draxin and Tsukushi are essential for forebrain commissure formation","volume":"374","author":"Hossain","year":"2013","journal-title":"Dev Biol"},{"key":"2022031309253106400_B17","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/j.bbrc.2010.10.127","article-title":"Tsukushi is required for anterior commissure formation in mouse brain","volume":"402","author":"Ito","year":"2010","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031309253106400_B18","doi-asserted-by":"crossref","first-page":"347","DOI":"10.1016\/j.devcel.2004.08.014","article-title":"Tsukushi functions as an organizer inducer by inhibition of BMP activity in cooperation with chordin","volume":"7","author":"Ohta","year":"2004","journal-title":"Dev Cell"},{"key":"2022031309253106400_B19","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1016\/j.molmet.2018.12.004","article-title":"Mapping the molecular signatures of diet-induced NASH and its regulation by the hepatokine Tsukushi","volume":"20","author":"Xiong","year":"2019","journal-title":"Mol Metab"},{"key":"2022031309253106400_B20","doi-asserted-by":"crossref","first-page":"G483","DOI":"10.1152\/ajpgi.00079.2013","article-title":"Diet-induced mouse model of fatty liver disease and nonalcoholic steatohepatitis reflecting clinical disease progression and methods of assessment","volume":"305","author":"Clapper","year":"2013","journal-title":"Am J Physiol Gastrointest Liver Physiol"},{"key":"2022031309253106400_B21","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1016\/j.molcel.2019.07.028","article-title":"Landscape of intercellular crosstalk in healthy and NASH liver revealed by single-cell secretome gene analysis","volume":"75","author":"Xiong","year":"2019","journal-title":"Mol Cell"},{"key":"2022031309253106400_B22","doi-asserted-by":"crossref","first-page":"7050","DOI":"10.1073\/pnas.1304707110","article-title":"Melanocortin-4 receptor mutations paradoxically reduce preference for palatable foods","volume":"110","author":"Panaro","year":"2013","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022031309253106400_B23","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1038\/s41467-020-16148-1","article-title":"BAF60a deficiency uncouples chromatin accessibility and cold sensitivity from white fat browning","volume":"11","author":"Liu","year":"2020","journal-title":"Nat Commun"},{"key":"2022031309253106400_B24","doi-asserted-by":"crossref","first-page":"1228","DOI":"10.1002\/hep.30921","article-title":"hnRNPU\/TrkB defines a chromatin accessibility checkpoint for liver injury and nonalcoholic steatohepatitis pathogenesis","volume":"71","author":"Xiong","year":"2020","journal-title":"Hepatology"},{"key":"2022031309253106400_B25","doi-asserted-by":"crossref","first-page":"4449","DOI":"10.1172\/JCI96324","article-title":"Hepatic neuregulin 4 signaling defines an endocrine checkpoint for steatosis-to-NASH progression","volume":"127","author":"Guo","year":"2017","journal-title":"J Clin Invest"},{"key":"2022031309253106400_B26","doi-asserted-by":"crossref","first-page":"4642","DOI":"10.1038\/emboj.2011.322","article-title":"Temporal orchestration of circadian autophagy rhythm by C\/EBP\u03b2","volume":"30","author":"Ma","year":"2011","journal-title":"EMBO J"},{"key":"2022031309253106400_B27","doi-asserted-by":"crossref","first-page":"288","DOI":"10.15252\/emmm.201404508","article-title":"Dual melanocortin-4 receptor and GLP-1 receptor agonism amplifies metabolic benefits in diet-induced obese mice","volume":"7","author":"Clemmensen","year":"2015","journal-title":"EMBO Mol Med"},{"key":"2022031309253106400_B28","doi-asserted-by":"crossref","first-page":"490","DOI":"10.2337\/db12-0598","article-title":"Chronic treatment with a melanocortin-4 receptor agonist causes weight loss, reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques","volume":"62","author":"Kievit","year":"2013","journal-title":"Diabetes"},{"key":"2022031309253106400_B29","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1006\/bbrc.1998.8389","article-title":"Selective antagonist for the melanocortin 4 receptor (HS014) increases food intake in free-feeding rats","volume":"245","author":"Kask","year":"1998","journal-title":"Biochem Biophys Res Commun"},{"key":"2022031309253106400_B30","doi-asserted-by":"crossref","first-page":"638","DOI":"10.1210\/en.2006-1233","article-title":"Importance of melanocortin signaling in refeeding-induced neuronal activation and satiety","volume":"148","author":"Singru","year":"2007","journal-title":"Endocrinology"},{"key":"2022031309253106400_B31","doi-asserted-by":"crossref","first-page":"890","DOI":"10.1210\/en.2010-0716","article-title":"Characterization of the hyperphagic response to dietary fat in the MC4R knockout mouse","volume":"152","author":"Srisai","year":"2011","journal-title":"Endocrinology"},{"key":"2022031309253106400_B32","doi-asserted-by":"crossref","first-page":"2454","DOI":"10.1016\/j.ajpath.2011.07.014","article-title":"Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis","volume":"179","author":"Itoh","year":"2011","journal-title":"Am J Pathol"},{"key":"2022031309253106400_B33","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1038\/nn.3737","article-title":"Melanocortin 4 receptors in autonomic neurons regulate thermogenesis and glycemia","volume":"17","author":"Berglund","year":"2014","journal-title":"Nat Neurosci"},{"key":"2022031309253106400_B34","doi-asserted-by":"crossref","first-page":"1550","DOI":"10.1210\/en.2006-1389","article-title":"Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue","volume":"148","author":"Voss-Andreae","year":"2007","journal-title":"Endocrinology"},{"key":"2022031309253106400_B35","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1016\/j.molmet.2019.09.014","article-title":"The hepatokine TSK does not affect brown fat thermogenic capacity, body weight gain, and glucose homeostasis","volume":"30","author":"Mouchiroud","year":"2019","journal-title":"Mol Metab"},{"key":"2022031309253106400_B36","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1007\/s12079-018-0452-8","article-title":"Involvement of Tsukushi in diverse developmental processes","volume":"12","author":"Ahmad","year":"2018","journal-title":"J Cell Commun Signal"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/70\/9\/2081\/627100\/db210161.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/70\/9\/2081\/627100\/db210161.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T12:42:32Z","timestamp":1667392952000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/70\/9\/2081\/137649\/Deletion-of-the-Feeding-Induced-Hepatokine-TSK"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,6,28]]},"references-count":36,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2021,6,28]]},"published-print":{"date-parts":[[2021,9,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db21-0161","relation":{"has-preprint":[{"id-type":"doi","id":"10.2337\/figshare.14806641.v1","asserted-by":"object"},{"id-type":"doi","id":"10.2337\/figshare.14806641","asserted-by":"object"}]},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,6,28]]}}}