{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:28:53Z","timestamp":1786969733770,"version":"build-2736575974"},"reference-count":59,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T00:00:00Z","timestamp":1786924800000},"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","award":["82170465"],"award-info":[{"award-number":["82170465"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82370404"],"award-info":[{"award-number":["82370404"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"award":["82170465"],"award-info":[{"award-number":["82170465"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]},{"award":["82370404"],"award-info":[{"award-number":["82370404"]}],"id":[{"id":"https:\/\/ror.org\/01h0zpd94","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Obesity-associated metabolic disorders are characterized by impaired glucose and lipid metabolism, insulin resistance, and adipose tissue dysfunction. Interferon regulatory factor 1 (IRF1) is a transcription factor primarily involved in immune regulation; however, its role in adipocyte metabolic regulation remains incompletely understood. In this study, adipocyte-specific Irf1 knockout (Irf1 AKO) mice were generated using the Cre\/loxP system and subjected to either a regular chow diet or a high-fat diet (HFD). Metabolic phenotyping, insulin signaling analysis, mitochondrial homeostasis-related assessment, and in vitro adipocyte experiments were performed. Adipocyte-specific IRF1 deficiency improved insulin-stimulated AKT phosphorylation in white adipose tissues and enhanced glucose tolerance and insulin sensitivity under HFD conditions. These metabolic improvements were accompanied by reduced oxygen consumption, energy expenditure, heat production, \u03b23-adrenergic-induced lipolytic response, and cold tolerance. At the molecular level, IRF1 deficiency was associated with reduced TOMM20 expression, decreased mtDNA content, downregulation of oxidative phosphorylation-related genes, and reduced ATP levels in adipose tissues, suggesting altered mitochondrial homeostasis. In 3T3-L1 adipocytes, IRF1 knockdown increased insulin-stimulated AKT activation, glucose uptake, and lipid accumulation, whereas IRF1 overexpression showed opposite trends. Collectively, these findings suggest that adipocyte IRF1 is associated with insulin signaling, lipid metabolic remodeling, and mitochondrial homeostasis, and highlight a potential dissociation between improved insulin responsiveness and reduced energy expenditure in diet-induced obesity.<\/jats:p>","DOI":"10.3390\/ijms27167332","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"7332","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["IRF1 in Adipocytes Is Associated with Insulin Signaling and Mitochondrial Homeostasis in Diet-Induced Obesity"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7145-9227","authenticated-orcid":false,"given":"Airan","family":"Zhu","sequence":"first","affiliation":[{"name":"Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ying","family":"Zhou","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaili","family":"Ren","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"ChongXiu","family":"Sun","sequence":"additional","affiliation":[{"name":"Collaborative Innovation Center for Cardiovascular Disease Translational Medicine, Nanjing Medical University, 101 Longmian Avenue, Jiangning District, Nanjing 211166, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/s41574-019-0176-8","article-title":"Obesity: Global epidemiology and pathogenesis","volume":"15","year":"2019","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1038\/nrm2391","article-title":"Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes","volume":"9","author":"Guilherme","year":"2008","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"852","DOI":"10.1016\/j.cell.2012.02.017","article-title":"Mechanisms for insulin resistance: Common threads and missing links","volume":"148","author":"Samuel","year":"2012","journal-title":"Cell"},{"key":"ref_4","first-page":"e984","article-title":"Obesity and Cardiovascular Disease: A Scientific Statement From the American Heart Association","volume":"143","author":"Poirier","year":"2021","journal-title":"Circulation"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.cell.2013.12.012","article-title":"What we talk about when we talk about fat","volume":"156","author":"Rosen","year":"2014","journal-title":"Cell"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1055\/s-0029-1192044","article-title":"Adipose Tissue Dysfunction in Obesity","volume":"117","year":"2009","journal-title":"Exp. Clin. Endocrinol. Diabetes"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1847","DOI":"10.1007\/s10620-008-0585-3","article-title":"Adipose tissue: The new endocrine organ? A review article","volume":"54","author":"Wozniak","year":"2009","journal-title":"Dig. Dis. Sci."},{"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","first-page":"733","DOI":"10.1111\/apha.12246","article-title":"Adipose tissue and its role in organ crosstalk","volume":"210","author":"Romacho","year":"2014","journal-title":"Acta Physiol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"6067349","DOI":"10.1155\/2016\/6067349","article-title":"Mitochondria in White, Brown, and Beige Adipocytes","volume":"2016","author":"Cedikova","year":"2016","journal-title":"Stem Cells Int."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"546","DOI":"10.1016\/j.cmet.2015.09.007","article-title":"Brown and Beige Fat: Physiological Roles beyond Heat Generation","volume":"22","author":"Kajimura","year":"2015","journal-title":"Cell Metab."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/j.tem.2018.01.001","article-title":"The Common and Distinct Features of Brown and Beige Adipocytes","volume":"29","author":"Ikeda","year":"2018","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"C375","DOI":"10.1152\/ajpcell.00379.2020","article-title":"Adipose tissue inflammation and metabolic dysfunction in obesity","volume":"320","author":"Kawai","year":"2021","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Zatterale, F., Longo, M., Naderi, J., Raciti, G.A., Desiderio, A., Miele, C., and Beguinot, F. (2019). Chronic Adipose Tissue Inflammation Linking Obesity to Insulin Resistance and Type 2 Diabetes. Front. Physiol., 10.","DOI":"10.3389\/fphys.2019.01607"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"247","DOI":"10.4093\/dmj.2018.0221","article-title":"Mitochondrial Dysfunction in Adipocytes as a Primary Cause of Adipose Tissue Inflammation","volume":"43","author":"Woo","year":"2019","journal-title":"Diabetes Metab. J."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"799","DOI":"10.1038\/414799a","article-title":"Insulin signalling and the regulation of glucose and lipid metabolism","volume":"414","author":"Saltiel","year":"2001","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1057","DOI":"10.1042\/BST20221066","article-title":"Insulin signalling and GLUT4 trafficking in insulin resistance","volume":"51","author":"Fazakerley","year":"2023","journal-title":"Biochem. Soc. Trans."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"a009191","DOI":"10.1101\/cshperspect.a009191","article-title":"Insulin receptor signaling in normal and insulin-resistant states","volume":"6","author":"Boucher","year":"2014","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"748","DOI":"10.1016\/j.cmet.2021.03.019","article-title":"Insulin action in adipocytes, adipose remodeling, and systemic effects","volume":"33","author":"Santoro","year":"2021","journal-title":"Cell Metab."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Girousse, A., Tavernier, G., Valle, C., Moro, C., Mejhert, N., Dinel, A.L., Houssier, M., Roussel, B., Besse-Patin, A., and Combes, M. (2013). Partial inhibition of adipose tissue lipolysis improves glucose metabolism and insulin sensitivity without alteration of fat mass. PLoS Biol., 11.","DOI":"10.1371\/journal.pbio.1001485"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"E653","DOI":"10.1152\/ajpendo.00620.2020","article-title":"100(th) anniversary of the discovery of insulin perspective: Insulin and adipose tissue fatty acid metabolism","volume":"320","author":"Carpentier","year":"2021","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"927","DOI":"10.2353\/ajpath.2009.081155","article-title":"Mitochondrial (dys)function in adipocyte (de)differentiation and systemic metabolic alterations","volume":"175","author":"Tejerina","year":"2009","journal-title":"Am. J. Pathol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Lee, J.H., Park, A., Oh, K.J., Lee, S.C., Kim, W.K., and Bae, K.H. (2019). The Role of Adipose Tissue Mitochondria: Regulation of Mitochondrial Function for the Treatment of Metabolic Diseases. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20194924"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Ikeda, K., and Yamada, T. (2020). UCP1 Dependent and Independent Thermogenesis in Brown and Beige Adipocytes. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00498"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"435","DOI":"10.1016\/j.tem.2012.06.004","article-title":"Mitochondrial dysfunction in white adipose tissue","volume":"23","author":"Kusminski","year":"2012","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1038\/nature12985","article-title":"Mitochondrial form and function","volume":"505","author":"Friedman","year":"2014","journal-title":"Nature"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1146\/annurev-biochem-060815-014352","article-title":"Mitochondrial Machineries for Protein Import and Assembly","volume":"86","author":"Wiedemann","year":"2017","journal-title":"Annu. Rev. Biochem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.lfs.2017.11.019","article-title":"Mitochondrial dysfunction in obesity","volume":"192","author":"Costa","year":"2018","journal-title":"Life Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"273","DOI":"10.1038\/s42255-024-00978-0","article-title":"Obesity causes mitochondrial fragmentation and dysfunction in white adipocytes due to RalA activation","volume":"6","author":"Xia","year":"2024","journal-title":"Nat. Metab."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"644","DOI":"10.1038\/nri1900","article-title":"IRFs: Master regulators of signalling by Toll-like receptors and cytosolic pattern-recognition receptors","volume":"6","author":"Honda","year":"2006","journal-title":"Nat. Rev. Immunol."},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Feng, H., Zhang, Y.B., Gui, J.F., Lemon, S.M., and Yamane, D. (2021). Interferon regulatory factor 1 (IRF1) and anti-pathogen innate immune responses. PLoS Pathog., 17.","DOI":"10.1371\/journal.ppat.1009220"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1038\/s41574-024-00990-0","article-title":"Transcriptional control of metabolism by interferon regulatory factors","volume":"20","author":"Ahmad","year":"2024","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1016\/j.cmet.2011.02.005","article-title":"Transcriptional control of adipose lipid handling by IRF4","volume":"13","author":"Eguchi","year":"2011","journal-title":"Cell Metab."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.cell.2014.04.049","article-title":"IRF4 is a key thermogenic transcriptional partner of PGC-1\u03b1","volume":"158","author":"Kong","year":"2014","journal-title":"Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2839","DOI":"10.1172\/JCI86080","article-title":"IRF3 promotes adipose inflammation and insulin resistance and represses browning","volume":"126","author":"Kumari","year":"2016","journal-title":"J. Clin. Investig."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"E485","DOI":"10.1152\/ajpendo.00505.2012","article-title":"Interferon regulatory factor 7 deficiency prevents diet-induced obesity and insulin resistance","volume":"305","author":"Wang","year":"2013","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"e144888","DOI":"10.1172\/JCI144888","article-title":"IRF3 reduces adipose thermogenesis via ISG15-mediated reprogramming of glycolysis","volume":"131","author":"Yan","year":"2021","journal-title":"J. Clin. Investig."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.stemcr.2017.03.014","article-title":"Activation of IRF1 in Human Adipocytes Leads to Phenotypes Associated with Metabolic Disease","volume":"8","author":"Friesen","year":"2017","journal-title":"Stem Cell Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2094","DOI":"10.1172\/JCI45887","article-title":"Adipose tissue remodeling and obesity","volume":"121","author":"Sun","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1172\/JCI88883","article-title":"The ominous triad of adipose tissue dysfunction: Inflammation, fibrosis, and impaired angiogenesis","volume":"127","author":"Crewe","year":"2017","journal-title":"J. Clin. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.2147\/DMSO.S250699","article-title":"Anti-Lipolysis Induced by Insulin in Diverse Pathophysiologic Conditions of Adipose Tissue","volume":"13","author":"Zhao","year":"2020","journal-title":"Diabetes Metab. Syndr. Obes."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1152\/physrev.00015.2003","article-title":"Brown adipose tissue: Function and physiological significance","volume":"84","author":"Cannon","year":"2004","journal-title":"Physiol. Rev."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1016\/j.tem.2013.12.004","article-title":"Brown fat fuel utilization and thermogenesis","volume":"25","author":"Townsend","year":"2014","journal-title":"Trends Endocrinol. Metab."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1016\/j.plipres.2009.05.001","article-title":"Lipolysis and lipid mobilization in human adipose tissue","volume":"48","author":"Lafontan","year":"2009","journal-title":"Prog. Lipid Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.mce.2009.08.031","article-title":"Sensory and sympathetic nervous system control of white adipose tissue lipolysis","volume":"318","author":"Bartness","year":"2010","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1252","DOI":"10.1038\/nm.3361","article-title":"Brown and beige fat: Development, function and therapeutic potential","volume":"19","author":"Harms","year":"2013","journal-title":"Nat. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Choe, S.S., Huh, J.Y., Hwang, I.J., Kim, J.I., and Kim, J.B. (2016). Adipose Tissue Remodeling: Its Role in Energy Metabolism and Metabolic Disorders. Front. Endocrinol., 7.","DOI":"10.3389\/fendo.2016.00030"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"R1177","DOI":"10.1016\/j.cub.2017.09.015","article-title":"The Origin and Diversification of Mitochondria","volume":"27","author":"Roger","year":"2017","journal-title":"Curr. Biol."},{"key":"ref_49","doi-asserted-by":"crossref","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":"ref_50","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1146\/annurev.biochem.76.052705.163409","article-title":"Translocation of proteins into mitochondria","volume":"76","author":"Neupert","year":"2007","journal-title":"Annu. Rev. Biochem."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"E1230","DOI":"10.1152\/ajpendo.00197.2003","article-title":"White adipose tissue contributes to UCP1-independent thermogenesis","volume":"285","author":"Granneman","year":"2003","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/nature17399","article-title":"Mitochondrial ROS regulate thermogenic energy expenditure and sulfenylation of UCP1","volume":"532","author":"Chouchani","year":"2016","journal-title":"Nature"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.cmet.2016.08.002","article-title":"Beige Adipocyte Maintenance Is Regulated by Autophagy-Induced Mitochondrial Clearance","volume":"24","author":"Shinoda","year":"2016","journal-title":"Cell Metab."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"eaai9248","DOI":"10.1126\/scisignal.aai9248","article-title":"Mitochondrial homeostasis in adipose tissue remodeling","volume":"10","author":"Kajimura","year":"2017","journal-title":"Sci. Signal"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1123","DOI":"10.15252\/embr.201643827","article-title":"Mfn2 deletion in brown adipose tissue protects from insulin resistance and impairs thermogenesis","volume":"18","author":"Mahdaviani","year":"2017","journal-title":"EMBO Rep."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"598","DOI":"10.1016\/j.cmet.2021.01.013","article-title":"A cold-stress-inducible PERK\/OGT axis controls TOM70-assisted mitochondrial protein import and cristae formation","volume":"33","author":"Bennett","year":"2021","journal-title":"Cell Metab."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"E667","DOI":"10.1152\/ajpendo.00282.2019","article-title":"Chronic arsenic exposure impairs adaptive thermogenesis in male C57BL\/6J mice","volume":"318","author":"Castriota","year":"2020","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"6344","DOI":"10.1038\/s41467-023-41988-y","article-title":"FAM210A is essential for cold-induced mitochondrial remodeling in brown adipocytes","volume":"14","author":"Qiu","year":"2023","journal-title":"Nat. Commun."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"R170","DOI":"10.1016\/j.cub.2018.01.004","article-title":"Mitophagy and Quality Control Mechanisms in Mitochondrial Maintenance","volume":"28","author":"Pickles","year":"2018","journal-title":"Curr. Biol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7332\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:11:24Z","timestamp":1786968684000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7332"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,17]]},"references-count":59,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167332"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167332","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,17]]}}}