{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,8]],"date-time":"2026-02-08T09:17:02Z","timestamp":1770542222408,"version":"3.49.0"},"reference-count":32,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T00:00:00Z","timestamp":1595203200000},"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-2015R1D1A1A01058699"],"award-info":[{"award-number":["NRF-2015R1D1A1A01058699"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Impaired glucose tolerance is a common feature associated with human aging, which is caused by defects in insulin secretion, insulin action or both. Recent studies have suggested that B-cell-activating factor (BAFF), a cytokine that modulates proliferation and differentiation of B cells, and its receptors are expressed in mature adipocytes and preadipocytes, proposing BAFF as a potential regulator of energy metabolism. In this study, we show that systemic BAFF depletion improves aging-dependent insulin resistance. In aged (10-month-old) BAFF\u2212\/\u2212 mice, glucose tolerance and insulin sensitivity were significantly improved despite higher adiposity as a result of expansion of adipose tissues compared to wild-type controls. BAFF\u2212\/\u2212 mice displayed an improved response to acute cold challenge, commensurate with the up-regulated expression of thermogenic genes in both brown and subcutaneous adipose tissues. These changes were found to be mediated by both increased M2-like (alternative) macrophage activation and enhanced leptin and FGF21 production, which may account for the improving effect of BAFF depletion on insulin resistance. In addition, leptin-deficient mice (ob\/ob) showed augmented BAFF signaling concomitant with impaired thermogenic activity, identifying BAFF as a suppressive factor to thermogenesis. Our findings suggest that suppression of BAFF could be a therapeutic approach to attenuate aging-dependent insulin resistance.<\/jats:p>","DOI":"10.3390\/ijms21145121","type":"journal-article","created":{"date-parts":[[2020,7,21]],"date-time":"2020-07-21T06:38:55Z","timestamp":1595313535000},"page":"5121","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["B-Cell-Activating Factor Depletion Ameliorates Aging-Dependent Insulin Resistance via Enhancement of Thermogenesis in Adipose Tissues"],"prefix":"10.3390","volume":"21","author":[{"given":"Bobae","family":"Kim","sequence":"first","affiliation":[{"name":"School of Life Science, Handong Global University, Pohang, Gyungbuk 37554, Korea"},{"name":"HEM Inc., Pohang, Gyungbuk 37554, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1862-8739","authenticated-orcid":false,"given":"Chang-Kee","family":"Hyun","sequence":"additional","affiliation":[{"name":"School of Life Science, Handong Global University, Pohang, Gyungbuk 37554, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1038\/nri2572","article-title":"Cracking the BAFF code","volume":"9","author":"Mackay","year":"2009","journal-title":"Nat. Rev. Immunol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"5948","DOI":"10.4049\/jimmunol.0901186","article-title":"Adipocytes as Immune Cells: Differential Expression of TWEAK, BAFF, and APRIL and Their Receptors (Fn14, BAFF-R, TACI, and BCMA) at Different Stages of Normal and Pathological Adipose Tissue Development","volume":"183","author":"Alexaki","year":"2009","journal-title":"J. Immunol."},{"key":"ref_3","first-page":"275","article-title":"B-cell activating factor (BAFF) \u2013 a new factor linking immunity to diet?","volume":"7","author":"Bienert","year":"2012","journal-title":"Cent. Eur. J. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s12072-012-9345-8","article-title":"B cell activating factor is associated with the histological severity of nonalcoholic fatty liver disease","volume":"7","author":"Miyake","year":"2013","journal-title":"Hepatol. Int."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1915","DOI":"10.1038\/oby.2011.165","article-title":"B Cell-Activating Factor Controls the Production of Adipokines and Induces Insulin Resistance","volume":"19","author":"Hamada","year":"2011","journal-title":"Obesity"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/labinvest.2012.176","article-title":"Blockade of B-cell-activating factor signaling enhances hepatic steatosis induced by a high-fat diet and improves insulin sensitivity","volume":"93","author":"Kawasaki","year":"2013","journal-title":"Lab. Investig."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-018-37403-y","article-title":"Depletion of B cell-activating factor attenuates hepatic fat accumulation in a murine model of nonalcoholic fatty liver disease","volume":"9","author":"Nakamura","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_8","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_9","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cmet.2018.11.002","article-title":"New advances in adaptive thermogenesis: UCP1 and beyond","volume":"29","author":"Chouchani","year":"2019","journal-title":"Cell Metab."},{"key":"ref_10","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_11","doi-asserted-by":"crossref","first-page":"1196","DOI":"10.1016\/j.celrep.2013.10.044","article-title":"UCP1 in brite\/beige adipose tissue mitochondria is functionally thermogenic","volume":"5","author":"Shabalina","year":"2013","journal-title":"Cell Rep."},{"key":"ref_12","first-page":"969","article-title":"Pharmacological and nutritional agents promoting browning of white adipose tissue","volume":"1831","author":"Bonet","year":"2013","journal-title":"Biochim. et Biophys. Acta (BBA) Mol. Cell Biol. Lipids"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"478","DOI":"10.1172\/JCI78362","article-title":"Brown and beige fat in humans: Thermogenic adipocytes that control energy and glucose homeostasis","volume":"125","author":"Sidossis","year":"2015","journal-title":"J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1016\/j.cell.2014.03.066","article-title":"Eosinophils and type 2 cytokine signaling in macrophages orchestrate development of functional beige fat","volume":"157","author":"Qiu","year":"2014","journal-title":"Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"576","DOI":"10.1038\/s41574-018-0059-4","article-title":"Inflammaging: A new immune-metabolic viewpoint for age-related diseases","volume":"14","author":"Franceschi","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"19","DOI":"10.3389\/fendo.2016.00019","article-title":"Browning and graying: Novel transcriptional regulators of brown and beige fat tissues and aging","volume":"7","author":"Mueller","year":"2016","journal-title":"Front. Endocrinol."},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Yang, P., Cui, R., Zhang, M., Li, H., Qian, C., Sheng, C., Qu, S., and Bu, L. (2015). Eosinophils reduce chronic inflammation in adipose tissue by secreting Th2 cytokines and promoting M2 macrophages polarization. Int. J. Endocrinol.","DOI":"10.1155\/2015\/565760"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Kim, B., and Hyun, C.K. (2016). Gender-specific mechanisms underlying the amelioration of high-fat diet-induced glucose intolerance in B-Cell-activating factor deficient mice. PLoS ONE.","DOI":"10.1371\/journal.pone.0166225"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1016\/S0303-7207(00)00313-0","article-title":"Leptin activates Stat3, Stat1 and AP-1 in mouse adipose tissue","volume":"168","author":"Bendinelli","year":"2000","journal-title":"Mol. Cell Endocrinol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"540","DOI":"10.1126\/science.7624776","article-title":"Effects of the obese gene product on body weight regulation in ob\/ob mice","volume":"269","author":"Pelleymounter","year":"1995","journal-title":"Science"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"109","DOI":"10.14336\/AD.2014.0305","article-title":"Metabolic syndrome, aging and involvement of oxidative stress","volume":"6","author":"Bonomini","year":"2015","journal-title":"Aging Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1171","DOI":"10.1016\/j.bbrc.2015.07.099","article-title":"B-cell-activating factor deficiency attenuates high-fat diet-induced glucose intolerance by potentiating adipose tissue function","volume":"464","author":"Kim","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Longo, M., Zatterale, F., Naderi, J., Parrillo, L., Formisano, P., Raciti, G.A., Beguinot, F., and Miele, C. (2019). Adipose tissue dysfunction as determinant of obesity-associated metabolic complications. Int. J. Mol. Sci.","DOI":"10.3390\/ijms20092358"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"268","DOI":"10.1016\/j.cmet.2010.03.007","article-title":"The changed metabolic world with human brown adipose tissue: Therapeutic visions","volume":"11","author":"Nedergaard","year":"2010","journal-title":"Cell Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2992","DOI":"10.1210\/en.2013-1403","article-title":"White, brown, beige\/brite: Different adipose cells for different functions?","volume":"154","author":"Giralt","year":"2013","journal-title":"Endocrinology"},{"key":"ref_26","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_27","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1126\/science.1201475","article-title":"Eosinophils sustain adipose alternatively activated macrophages associated with glucose homeostasis","volume":"332","author":"Wu","year":"2011","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1038\/nature10653","article-title":"Alternatively activated macrophages produce catecholamines to sustain adaptive thermogenesis","volume":"480","author":"Nguyen","year":"2011","journal-title":"Nature"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3389\/fphys.2019.00037","article-title":"Fibroblast growth factor 21 and browning of white adipose tissue","volume":"10","author":"Mehta","year":"2019","journal-title":"Front. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3688","DOI":"10.1210\/endo.140.8.6890","article-title":"Effects of intravenously infused leptin on insulin sensitivity and on the expression of uncoupling proteins in brown adipose tissue","volume":"140","author":"Rouru","year":"1999","journal-title":"Endocrinology"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1038\/cr.2010.177","article-title":"Non-canonical NF-\u03baB signaling pathway","volume":"21","author":"Sun","year":"2011","journal-title":"Cell Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/ijo.2015.198","article-title":"Classical and alternative NF-\u03baB signaling cooperate in regulating adipocyte differentiation and function","volume":"40","author":"Weidemann","year":"2016","journal-title":"Int. J. Obes."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/5121\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:50:08Z","timestamp":1760176208000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/5121"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,20]]},"references-count":32,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["ijms21145121"],"URL":"https:\/\/doi.org\/10.3390\/ijms21145121","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,20]]}}}