{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T06:09:12Z","timestamp":1771049352788,"version":"3.50.1"},"reference-count":28,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-2022R1A2C2006224"],"award-info":[{"award-number":["NRF-2022R1A2C2006224"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["NRF-RS2023-00222784"],"award-info":[{"award-number":["NRF-RS2023-00222784"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100020448","name":"Korean Society for the Study of Obesity","doi-asserted-by":"crossref","award":["KSSO202401"],"award-info":[{"award-number":["KSSO202401"]}],"id":[{"id":"10.13039\/100020448","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Korean Diabetes Association Grant","award":["2017F-4"],"award-info":[{"award-number":["2017F-4"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adipose tissue macrophages (ATMs) are key mediators of obesity-induced inflammation and insulin resistance. However, the contribution of lysosomal dysfunction to ATM inflammatory activation remains poorly defined. Here, we characterized lysosomal structural and functional alterations in ATMs during obesity and examined whether pharmacological restoration of lysosomal function using 2-hydroxypropyl-\u03b2-cyclodextrin (HP\u03b2CD) ameliorates metabolic inflammation. In diet-induced obese C57BL\/6J male mice, adipose tissue exhibited increased lysosomal abundance, accompanied by reduced cathepsin L+V expression, modestly increased lysosomal acid lipase levels, and decreased expression of transcription factor EB (TFEB), a master regulator of lysosomal biogenesis. Despite expanded lysosomal content, ATMs displayed impaired lysosomal acidification, indicating functional lysosomal dysfunction. Intraperitoneal administration of HP\u03b2CD for two weeks significantly improved glucose tolerance and insulin sensitivity without affecting body weight. Flow cytometric analysis revealed reduced pro-inflammatory M1 ATMs and CD8+ T lymphocytes in visceral adipose tissue, whereas immune cell populations in subcutaneous adipose tissue, blood, and spleen remained unchanged. In vitro, HP\u03b2CD suppressed pro-inflammatory gene expression in both classically and metabolically activated macrophages and attenuated inflammatory responses induced by lysosomal stressors, including bafilomycin A1 and chloroquine, while restoring TFEB expression. Collectively, these findings demonstrate that obesity is associated with lysosomal dysfunction in ATMs and that restoration of lysosomal function alleviates adipose tissue inflammation and metabolic dysfunction, highlighting lysosomal regulation in ATMs as a potential therapeutic target for obesity-associated metabolic diseases.<\/jats:p>","DOI":"10.3390\/ijms27041755","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T09:48:34Z","timestamp":1770889714000},"page":"1755","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Restoring Lysosomes in Adipose Tissue Macrophages Mitigates Obesity-Induced Inflammation and Insulin Resistance"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4490-5314","authenticated-orcid":false,"given":"Jiyeon","family":"Chang","sequence":"first","affiliation":[{"name":"Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea"},{"name":"Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ellen","family":"Budiono","sequence":"additional","affiliation":[{"name":"Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea"},{"name":"Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5252-893X","authenticated-orcid":false,"given":"Shindy","family":"Soedono","sequence":"additional","affiliation":[{"name":"Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea"},{"name":"Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-9563-5966","authenticated-orcid":false,"given":"Xaviera Riani","family":"Yasasilka","sequence":"additional","affiliation":[{"name":"Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea"},{"name":"Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"SungWan","family":"Chun","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan 31151, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7512-6722","authenticated-orcid":false,"given":"Kae Won","family":"Cho","sequence":"additional","affiliation":[{"name":"Department of Integrated Biomedical Science, Soonchunhyang University, Cheonan 31151, Republic of Korea"},{"name":"Soonchunhyang Institute of Medi-Bio Science (SIMS), Soonchunhyang University, Cheonan 31151, Republic of Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,12]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1668","DOI":"10.1080\/15548627.2019.1703355","article-title":"Sustained activation of autophagy suppresses adipocyte maturation via a lipolysis-dependent mechanism","volume":"16","author":"Zhang","year":"2020","journal-title":"Autophagy"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1016\/j.immuni.2014.06.008","article-title":"Macrophage activation and polarization: Nomenclature and experimental guidelines","volume":"41","author":"Murray","year":"2014","journal-title":"Immunity"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1172\/JCI29881","article-title":"Obesity induces a phenotypic switch in adipose tissue macrophage polarization","volume":"117","author":"Lumeng","year":"2007","journal-title":"J. Clin. Investig."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Castoldi, A., Naffah de Souza, C., C\u00e2mara, N.O., and Moraes-Vieira, P.M. (2015). The Macrophage Switch in Obesity Development. Front. Immunol., 6.","DOI":"10.3389\/fimmu.2015.00637"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1494","DOI":"10.1172\/JCI26498","article-title":"MCP-1 contributes to macrophage infiltration into adipose tissue, insulin resistance, and hepatic steatosis in obesity","volume":"116","author":"Kanda","year":"2006","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1420","DOI":"10.1038\/sj.ijo.0803632","article-title":"Human adipose tissue macrophages are of an anti-inflammatory phenotype but capable of excessive pro-inflammatory mediator production","volume":"31","author":"Zeyda","year":"2007","journal-title":"Int. J. Obes."},{"key":"ref_7","first-page":"154936","article-title":"Distinct lysosome phenotypes influence inflammatory function in peritoneal and bone marrow-derived macrophages","volume":"2014","author":"Weber","year":"2014","journal-title":"Int. J. Inflamm."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.cmet.2013.11.001","article-title":"Obesity activates a program of lysosomal-dependent lipid metabolism in adipose tissue macrophages independently of classic activation","volume":"18","author":"Xu","year":"2013","journal-title":"Cell Metab."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Cabrera-Reyes, F., Parra-Ruiz, C., Yuseff, M.I., and Zanlungo, S. (2021). Alterations in Lysosome Homeostasis in Lipid-Related Disorders: Impact on Metabolic Tissues and Immune Cells. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.790568"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s13679-025-00638-8","article-title":"Autolysosomal Dysfunction in Obesity-induced Metabolic Inflammation and Related Disorders","volume":"14","author":"Cheong","year":"2025","journal-title":"Curr. Obes. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1126\/science.1174447","article-title":"A gene network regulating lysosomal biogenesis and function","volume":"325","author":"Sardiello","year":"2009","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1038\/s41569-024-01072-4","article-title":"Lysosomes in the immunometabolic reprogramming of immune cells in atherosclerosis","volume":"22","author":"Bonacina","year":"2025","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1942","DOI":"10.1161\/ATVBAHA.114.303342","article-title":"Induction of lysosomal biogenesis in atherosclerotic macrophages can rescue lipid-induced lysosomal dysfunction and downstream sequelae","volume":"34","author":"Emanuel","year":"2014","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"114617","DOI":"10.1016\/j.addr.2022.114617","article-title":"Cyclodextrins applied to the treatment of lysosomal storage disorders","volume":"191","author":"Ishitsuka","year":"2022","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"5477","DOI":"10.1073\/pnas.0914309107","article-title":"Endocytosis of beta-cyclodextrins is responsible for cholesterol reduction in Niemann-Pick type C mutant cells","volume":"107","author":"Rosenbaum","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"10211","DOI":"10.1074\/jbc.M113.506246","article-title":"2-Hydroxypropyl-\u03b2-cyclodextrin promotes transcription factor EB-mediated activation of autophagy: Implications for therapy","volume":"289","author":"Song","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"16026","DOI":"10.1074\/jbc.271.27.16026","article-title":"Cellular cholesterol efflux mediated by cyclodextrins. Demonstration Of kinetic pools and mechanism of efflux","volume":"271","author":"Yancey","year":"1996","journal-title":"J. Biol. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1523\/JNEUROSCI.0933-21.2021","article-title":"Repeated administration of 2-hydroxypropyl-\u03b2-cyclodextrin (HP\u03b2CD) attenuates the chronic inflammatory response to experimental stroke","volume":"42","author":"Becktel","year":"2022","journal-title":"J. Neurosci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1038\/s41574-023-00908-2","article-title":"Macrophage and T cell networks in adipose tissue","volume":"20","author":"Jacks","year":"2024","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1016\/j.tcb.2014.06.006","article-title":"Lysosome: Regulator of lipid degradation pathways","volume":"24","author":"Settembre","year":"2014","journal-title":"Trends Cell Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3310","DOI":"10.2337\/db13-1720","article-title":"Lysosomal stress in obese adipose tissue macrophages contributes to MITF-dependent Gpnmb induction","volume":"63","author":"Gabriel","year":"2014","journal-title":"Diabetes"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"2779","DOI":"10.1038\/s41467-024-47108-8","article-title":"TM4SF19-mediated control of lysosomal activity in macrophages contributes to obesity-induced inflammation and metabolic dysfunction","volume":"15","author":"Choi","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","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":"ref_24","doi-asserted-by":"crossref","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":"ref_25","doi-asserted-by":"crossref","first-page":"254","DOI":"10.1159\/000515035","article-title":"Lysosome Depletion-Triggered Autophagy Impairment in Progressive Kidney Injury","volume":"7","author":"Chen","year":"2021","journal-title":"Kidney Dis."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/s41419-020-03032-5","article-title":"Lysosomal quality control of cell fate: A novel therapeutic target for human diseases","volume":"11","author":"Zhu","year":"2020","journal-title":"Cell Death Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1302","DOI":"10.1016\/j.celrep.2013.10.042","article-title":"Impaired autophagy in the lipid-storage disorder Niemann-Pick type C1 disease","volume":"5","author":"Sarkar","year":"2013","journal-title":"Cell Rep."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"333ra350","DOI":"10.1126\/scitranslmed.aad6100","article-title":"Cyclodextrin promotes atherosclerosis regression via macrophage reprogramming","volume":"8","author":"Zimmer","year":"2016","journal-title":"Sci. Transl. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1755\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,14]],"date-time":"2026-02-14T05:31:04Z","timestamp":1771047064000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/4\/1755"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,12]]},"references-count":28,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["ijms27041755"],"URL":"https:\/\/doi.org\/10.3390\/ijms27041755","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,12]]}}}