{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,2]],"date-time":"2026-06-02T08:48:28Z","timestamp":1780390108026,"version":"3.54.1"},"reference-count":53,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Vet. Sci."],"abstract":"<jats:p>Excessive lipid mobilization for adipose tissue caused by severe negative energy balance is the pathological basis for subclinical ketosis (SCK) in dairy cows. In non-ruminants, transcription factor EB (TFEB) was reported to play a role in the regulation of lipid catabolism, but its role in the control of lipolysis in the bovine is unknown. The present study aimed to determine whether the enhanced TFEB transcriptional activity contributes to lipolysis of adipose tissue in SCK cows, and to explore the possibility of establishing a therapeutic strategy by using TFEB as a target to control lipolysis. Thirty cows with similar lactation number (media<jats:italic>n<\/jats:italic> = 3, range = 2\u20134) and days in milk (media<jats:italic>n<\/jats:italic> = 6 d, range = 3\u20139) were selected into a healthy control (<jats:italic>n<\/jats:italic> = 15) and SCK (<jats:italic>n<\/jats:italic> = 15) group, and used for subcutaneous adipose tissue biopsies and blood sampling. Adipocytes from healthy Holstein calves were used as a model for <jats:italic>in vitro<\/jats:italic> studies involving treatment with 10 \u03bc<jats:italic>M<\/jats:italic> isoproterenol (ISO) for 0, 1, 2 and 3 h, 250 n<jats:italic>M<\/jats:italic> of the TFEB activator Torin1 for 3 h, or used for transfection with TFEB small interfering RNA for 48 h followed by treatment with 10 \u03bc<jats:italic>M<\/jats:italic> ISO for 3 h. Compared with healthy cows, adipose tissue in SCK cows showed increased lipolysis accompanied by enhanced TFEB transcriptional activity. <jats:italic>In vitro<\/jats:italic>, ISO and Torin1 treatment increased lipolysis and enhanced TFEB transcriptional activity in calf adipocytes. However, knockdown of <jats:italic>TFEB<\/jats:italic> attenuated ISO-induced lipolysis in adipocytes. Overall, these findings indicated that enhanced transcriptional activity of TFEB may contribute to lipolysis of adipose tissue in dairy cows with SCK. The regulation of TFEB activity may be an effective therapeutic strategy for controlling overt lipolysis in ketotic cows.<\/jats:p>","DOI":"10.3389\/fvets.2022.816064","type":"journal-article","created":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T05:32:04Z","timestamp":1644298324000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Activation of Transcription Factor EB Is Associated With Adipose Tissue Lipolysis in Dairy Cows With Subclinical Ketosis"],"prefix":"10.3389","volume":"9","author":[{"given":"Hao","family":"Yu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinxing","family":"Gao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan J.","family":"Loor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianming","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiyuan","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Hao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Shi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minghe","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinwei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guowen","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhe","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaobing","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiliang","family":"Du","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"323","DOI":"10.4081\/ijas.2005.323","article-title":"Physiological and pathological adaptations in dairy cows that may increase susceptibility to periparturient diseases and disorders","volume":"4","author":"Drackley","year":"2005","journal-title":"Ital J Anim Sci."},{"key":"B2","doi-asserted-by":"publisher","first-page":"11175","DOI":"10.3168\/jds.2018-15120","article-title":"Impaired hepatic autophagic activity in dairy cows with severe fatty liver is associated with inflammation and reduced liver function","volume":"101","author":"Du","year":"2018","journal-title":"J Dairy Sci."},{"key":"B3","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1111\/rda.12608","article-title":"Influence of body condition on serum metabolic indicators of lipid mobilization and oxidative stress in dairy cows during the transition period","volume":"50","author":"Folnozic","year":"2015","journal-title":"Reprod Domest Anim."},{"key":"B4","doi-asserted-by":"publisher","first-page":"2259","DOI":"10.3168\/jds.S0022-0302(99)75474-3","article-title":"ADSA foundation scholar award. Biology of dairy cows during the transition period: the final frontier?","volume":"82","author":"Drackley","year":"1999","journal-title":"J Dairy Sci."},{"key":"B5","doi-asserted-by":"publisher","first-page":"e12958","DOI":"10.1111\/obr.12958","article-title":"White adipose tissue mitochondrial metabolism in health and in obesity","volume":"21","author":"Heinonen","year":"2020","journal-title":"Obes Rev."},{"key":"B6","doi-asserted-by":"publisher","first-page":"238","DOI":"10.1186\/s12917-021-02947-1","article-title":"Oxidative status in dairy goats: periparturient variation and changes in subclinical hyperketonemia and hypocalcemia","volume":"17","author":"Huang","year":"2021","journal-title":"BMC Vet Res."},{"key":"B7","doi-asserted-by":"publisher","first-page":"583","DOI":"10.3168\/jds.S0022-0302(01)74511-0","article-title":"Ketone bodies in milk and blood of dairy cows: relationship between concentrations and utilization for detection of subclinical ketosis","volume":"84","author":"Enjalbert","year":"2001","journal-title":"J Dairy Sci."},{"key":"B8","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1016\/S0749-0720(15)30102-X","article-title":"Ruminant adaptation to negative energy balance. Influences on the etiology of ketosis and fatty liver","volume":"16","author":"Herdt","year":"2000","journal-title":"Vet Clin North Am Food Anim Pract."},{"key":"B9","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1152\/physiolgenomics.00188.2007","article-title":"Nutrition-induced ketosis alters metabolic and signaling gene networks in liver of periparturient dairy cows","volume":"32","author":"Loor","year":"2007","journal-title":"Physiol Genomics."},{"key":"B10","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1038\/ncb2718","article-title":"TFEB controls cellular lipid metabolism through a starvation-induced autoregulatory loop","volume":"15","author":"Settembre","year":"2013","journal-title":"Nat Cell Biol."},{"key":"B11","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1146\/annurev.genet.38.072902.092717","article-title":"Melanocytes and the Microphthalmia transcription factor network","volume":"38","author":"Steingrimsson","year":"2004","journal-title":"Annu Rev Genet."},{"key":"B12","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1038\/s41467-018-03340-7","article-title":"MAP4K3 mediates amino acid-dependent regulation of autophagy via phosphorylation of TFEB","volume":"9","author":"Hsu","year":"2018","journal-title":"Nat Commun."},{"key":"B13","doi-asserted-by":"publisher","first-page":"1429","DOI":"10.1126\/science.1204592","article-title":"TFEB links autophagy to lysosomal biogenesis","volume":"332","author":"Settembre","year":"2011","journal-title":"Science."},{"key":"B14","doi-asserted-by":"publisher","first-page":"1017","DOI":"10.1080\/15548627.2019.1569928","article-title":"YWHA\/14-3-3 proteins recognize phosphorylated TFEB by a noncanonical mode for controlling TFEB cytoplasmic localization","volume":"15","author":"Xu","year":"2019","journal-title":"Autophagy."},{"key":"B15","doi-asserted-by":"publisher","first-page":"288","DOI":"10.1038\/ncb3114","article-title":"Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB","volume":"17","author":"Medina","year":"2015","journal-title":"Nat Cell Biol."},{"key":"B16","doi-asserted-by":"publisher","first-page":"G509","DOI":"10.1152\/ajpgi.00376.2018","article-title":"Ethanol withdrawal mitigates fatty liver by normalizing lipid catabolism","volume":"316","author":"Thomes","year":"2019","journal-title":"Am J Physiol-Gastr L."},{"key":"B17","doi-asserted-by":"publisher","first-page":"2281","DOI":"10.1126\/scisignal.aau2281","article-title":"TFEB drives PGC-1alpha expression in adipocytes to protect against diet-induced metabolic dysfunction","volume":"12","author":"Evans","year":"2019","journal-title":"Sci Signal."},{"key":"B18","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1080\/15548627.2018.1434373","article-title":"TFEB and trehalose drive the macrophage autophagy-lysosome system to protect against atherosclerosis","volume":"14","author":"Evans","year":"2018","journal-title":"Autophagy."},{"key":"B19","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1080\/15548627.2018.1511504","article-title":"TFEB-driven endocytosis coordinates MTORC1 signaling and autophagy","volume":"15","author":"Nnah","year":"2019","journal-title":"Autophagy."},{"key":"B20","doi-asserted-by":"publisher","first-page":"4516","DOI":"10.3168\/jds.2020-18728","article-title":"Adenosine 5'-monophosphate-activated protein kinase ameliorates bovine adipocyte oxidative stress by inducing antioxidant responses and autophagy","volume":"104","author":"Xu","year":"2021","journal-title":"J Dairy Sci."},{"key":"B21","doi-asserted-by":"publisher","first-page":"668","DOI":"10.1038\/ncb2741","article-title":"MXL-3 and HLH-30 transcriptionally link lipolysis and autophagy to nutrient availability","volume":"15","author":"O'Rourke","year":"2013","journal-title":"Nat Cell Biol."},{"key":"B22","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1080\/15548627.2016.1271514","article-title":"Multistep regulation of TFEB by MTORC1","volume":"13","author":"Vega-Rubin-de-Celis","year":"2017","journal-title":"Autophagy."},{"key":"B23","doi-asserted-by":"publisher","first-page":"4847","DOI":"10.3168\/jds.2020-19150","article-title":"Hepatic autophagy and mitophagy status in dairy cows with subclinical and clinical ketosis","volume":"104","author":"Shen","year":"2021","journal-title":"J Dairy Sci."},{"key":"B24","doi-asserted-by":"publisher","first-page":"3476","DOI":"10.3168\/jds.2017-13234","article-title":"High concentrations of fatty acids and beta-hydroxybutyrate impair the growth hormone-mediated hepatic JAK2-STAT5 pathway in clinically ketotic cows","volume":"101","author":"Du","year":"2018","journal-title":"J Dairy Sci."},{"key":"B25","doi-asserted-by":"publisher","first-page":"6011","DOI":"10.3168\/jds.2011-4463","article-title":"A field trial on the effect of propylene glycol on milk yield and resolution of ketosis in fresh cows diagnosed with subclinical ketosis","volume":"94","author":"Mcart","year":"2011","journal-title":"J Dairy Sci."},{"key":"B26","doi-asserted-by":"publisher","first-page":"5656","DOI":"10.3168\/jds.2012-6142","article-title":"Periparturient dairy cows do not exhibit hepatic insulin resistance, yet adipose-specific insulin resistance occurs in cows prone to high weight loss","volume":"96","author":"Zachut","year":"2013","journal-title":"J Dairy Sci."},{"key":"B27","doi-asserted-by":"publisher","first-page":"48","DOI":"10.1186\/s12917-019-1791-2","article-title":"All-trans retinoic acid inhibits lipopolysaccharide-induced inflammatory responses in bovine adipocytes via TGFbeta1\/Smad3 signaling pathway","volume":"15","author":"Xu","year":"2019","journal-title":"Bmc Vet Res"},{"key":"B28","doi-asserted-by":"publisher","first-page":"407","DOI":"10.1016\/j.cmet.2017.07.012","article-title":"Triglyceride synthesis by DGAT1 protects adipocytes from lipid-induced ER stress during lipolysis","volume":"26","author":"Chitraju","year":"2017","journal-title":"Cell Metab."},{"key":"B29","doi-asserted-by":"publisher","first-page":"527","DOI":"10.1007\/s00726-018-2550-6","article-title":"Taurine is an amino acid with the ability to activate autophagy in adipocytes","volume":"50","author":"Kaneko","year":"2018","journal-title":"Amino Acids."},{"key":"B30","doi-asserted-by":"publisher","first-page":"408","DOI":"10.1016\/j.cell.2011.06.034","article-title":"mTOR complex 1 regulates lipin 1 localization to control the SREBP pathway","volume":"146","author":"Peterson","year":"2011","journal-title":"Cell."},{"key":"B31","doi-asserted-by":"publisher","first-page":"6246","DOI":"10.1002\/jcp.29553","article-title":"Effects of different fatty acids on BRL3A rat liver cell damage","volume":"235","author":"Yang","year":"2020","journal-title":"J Cell Physiol."},{"key":"B32","doi-asserted-by":"publisher","first-page":"108214","DOI":"10.1016\/j.jnutbio.2019.07.005","article-title":"Formononetin alleviates hepatic steatosis by facilitating TFEB-mediated lysosome biogenesis and lipophagy","volume":"73","author":"Wang","year":"2019","journal-title":"J Nutr Biochem."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1529","DOI":"10.1172\/JCI141529","article-title":"Stabilization of fatty acid synthesis enzyme acetyl-CoA carboxylase 1 suppresses acute myeloid leukemia development","volume":"131","author":"Ito","year":"2021","journal-title":"J Clin Invest."},{"key":"B34","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1016\/S0022-2275(20)38845-3","article-title":"Adaptations in lipid metabolism of bovine adipose tissue in lactogenesis and lactation","volume":"27","author":"McNamara","year":"1986","journal-title":"J Lipid Res."},{"key":"B35","doi-asserted-by":"publisher","first-page":"6134","DOI":"10.3168\/jds.2020-19319","article-title":"Inhibition of cell death inducing DNA fragmentation factor-alpha-like effector c (CIDEC) by tumor necrosis factor-alpha induces lipolysis and inflammation in calf adipocytes","volume":"104","author":"Fan","year":"2021","journal-title":"J Dairy Sci."},{"key":"B36","doi-asserted-by":"publisher","first-page":"447","DOI":"10.1016\/j.cvfa.2004.06.013","article-title":"Dry matter intake and energy balance in the transition period","volume":"20","author":"Grummer","year":"2004","journal-title":"Vet Clin North Am Food Anim Pract."},{"key":"B37","doi-asserted-by":"publisher","first-page":"E879","DOI":"10.1152\/ajpendo.00530.2014","article-title":"Adipose triglyceride lipase deletion from adipocytes, but not skeletal myocytes, impairs acute exercise performance in mice","volume":"308","author":"Dub\u00e9","year":"2015","journal-title":"Am J Physiol Endocrinol Metab."},{"key":"B38","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/0065-2571(94)90022-1","article-title":"The multifunctional role of hormone-sensitive lipase in lipid metabolism","volume":"34","author":"Yeaman","year":"1994","journal-title":"Adv Enzyme Regul."},{"key":"B39","doi-asserted-by":"publisher","first-page":"1383","DOI":"10.1126\/science.1100747","article-title":"Fat mobilization in adipose tissue is promoted by adipose triglyceride lipase","volume":"306","author":"Zimmermann","year":"2004","journal-title":"Science."},{"key":"B40","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1590\/2359-3997000000067","article-title":"Lipolysis and lipases in white adipose tissue - An update","volume":"59","author":"Bolsoni-Lopes","year":"2015","journal-title":"Arch Endocrinol Metab."},{"key":"B41","doi-asserted-by":"publisher","first-page":"3610","DOI":"10.1210\/en.2015-1322","article-title":"Impact of reduced ATGL-mediated adipocyte lipolysis on obesity-associated insulin resistance and inflammation in male mice","volume":"156","author":"Schoiswohl","year":"2015","journal-title":"Endocrinology."},{"key":"B42","doi-asserted-by":"publisher","first-page":"4514","DOI":"10.3168\/jds.2011-4145","article-title":"Hormone-sensitive lipase protein expression and extent of phosphorylation in subcutaneous and retroperitoneal adipose tissues in the periparturient dairy cow","volume":"94","author":"Locher","year":"2011","journal-title":"J Dairy Sci."},{"key":"B43","doi-asserted-by":"publisher","first-page":"1379","DOI":"10.4161\/auto.7.11.17166","article-title":"TFEB regulates autophagy: an integrated coordination of cellular degradation and recycling processes","volume":"7","author":"Settembre","year":"2011","journal-title":"Autophagy."},{"key":"B44","doi-asserted-by":"publisher","first-page":"3312","DOI":"10.1038\/s41467-018-05862-6","article-title":"mTOR-dependent phosphorylation controls TFEB nuclear export","volume":"9","author":"Napolitano","year":"2018","journal-title":"Nat Commun."},{"key":"B45","doi-asserted-by":"publisher","first-page":"1095","DOI":"10.1038\/emboj.2012.32","article-title":"A lysosome-to-nucleus signalling mechanism senses and regulates the lysosome via mTOR and TFEB","volume":"31","author":"Settembre","year":"2012","journal-title":"Embo J."},{"key":"B46","doi-asserted-by":"publisher","first-page":"e602574","DOI":"10.3389\/fcell.2020.602574","article-title":"Liraglutide alleviates hepatic steatosis by activating the TFEB-regulated autophagy-lysosomal pathway","volume":"8","author":"Fang","year":"2020","journal-title":"Front Cell Dev Biol."},{"key":"B47","doi-asserted-by":"publisher","first-page":"433","DOI":"10.1016\/j.rvsc.2012.11.009","article-title":"Effects of \u03b2-hydroxybutyrate and isoproterenol on lipolysis in isolated adipocytes from periparturient dairy cows and cows with clinical ketosis","volume":"94","author":"van der Drift","year":"2013","journal-title":"Res Vet Sci."},{"key":"B48","doi-asserted-by":"publisher","first-page":"1065","DOI":"10.1038\/ncb3407","article-title":"Protein kinase C controls lysosome biogenesis independently of mTORC1","volume":"18","author":"Li","year":"2016","journal-title":"Nat Cell Biol."},{"key":"B49","doi-asserted-by":"publisher","first-page":"605","DOI":"10.15252\/emmm.201607204","article-title":"TFE3 regulates whole-body energy metabolism in cooperation with TFEB","volume":"9","author":"Pastore","year":"2017","journal-title":"EMBO Mol Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"553","DOI":"10.1038\/nature18014","article-title":"AMPK-SKP2-CARM1 signalling cascade in transcriptional regulation of autophagy","volume":"534","author":"Shin","year":"2016","journal-title":"Nature."},{"key":"B51","doi-asserted-by":"publisher","first-page":"1131","DOI":"10.1038\/nature07976","article-title":"Autophagy regulates lipid metabolism","volume":"458","author":"Singh","year":"2009","journal-title":"Nature."},{"key":"B52","doi-asserted-by":"publisher","first-page":"ra9","DOI":"10.1126\/scisignal.2004754","article-title":"The nutrient-responsive transcription factor TFE3 promotes autophagy, lysosomal biogenesis, and clearance of cellular debris","volume":"7","author":"Martina","year":"2014","journal-title":"Sci Signal."},{"key":"B53","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1146\/annurev-cellbio-111315-125407","article-title":"TFEB and TFE3: linking lysosomes to cellular adaptation to stress","volume":"32","author":"Raben","year":"2016","journal-title":"Annu Rev Cell Dev Biol."}],"container-title":["Frontiers in Veterinary Science"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2022.816064\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T05:32:07Z","timestamp":1644298327000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fvets.2022.816064\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,8]]},"references-count":53,"alternative-id":["10.3389\/fvets.2022.816064"],"URL":"https:\/\/doi.org\/10.3389\/fvets.2022.816064","relation":{},"ISSN":["2297-1769"],"issn-type":[{"value":"2297-1769","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,8]]},"article-number":"816064"}}