{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:00:24Z","timestamp":1792789224088,"version":"4.5.0"},"reference-count":39,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T00:00:00Z","timestamp":1790726400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["0.58275\/AHA.25CDA1446568.pc.gr.229614"],"award-info":[{"award-number":["0.58275\/AHA.25CDA1446568.pc.gr.229614"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000968","name":"American Heart Association","doi-asserted-by":"publisher","award":["No. 26POST1562389"],"award-info":[{"award-number":["No. 26POST1562389"]}],"id":[{"id":"10.13039\/100000968","id-type":"DOI","asserted-by":"publisher"}]},{"award":["0.58275\/AHA.25CDA1446568.pc.gr.229614"],"award-info":[{"award-number":["0.58275\/AHA.25CDA1446568.pc.gr.229614"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]},{"award":["No. 26POST1562389"],"award-info":[{"award-number":["No. 26POST1562389"]}],"id":[{"id":"https:\/\/ror.org\/013kjyp64","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Department of Science and Technology of Hunan Province","award":["No. 2025JJ70115"],"award-info":[{"award-number":["No. 2025JJ70115"]}],"id":[{"id":"https:\/\/ror.org\/04qgr7x96","id-type":"ROR","asserted-by":"crossref"}]},{"award":["No. 2025JJ70115"],"award-info":[{"award-number":["No. 2025JJ70115"]}],"id":[{"id":"https:\/\/ror.org\/04qgr7x96","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007270","name":"University of Michigan","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007270","id-type":"DOI","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/00jmfr291","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Perivascular adipose tissue (PVAT) is increasingly recognized as an active vascular regulator that influences inflammation, metabolism, and atherosclerotic progression. In healthy vessels, PVAT displays brown adipose-like features and contributes to vascular protection, whereas PVAT dysfunction is associated with adipose whitening, inflammatory activation, and enhanced plaque formation. Circadian clock genes are major regulators of tissue metabolism, yet their role in PVAT biology and atherosclerosis remains incompletely understood. Here, we investigated the function of the core circadian factor BMAL1 in brown adipocytes and PVAT using a brown adipocyte-specific BMAL1 knockout model (Bmal1BAKO) and ApoE-deficient atherosclerosis-prone mice. Transcriptomic profiling of thoracic aortic PVAT and abdominal aortic PVAT revealed that BMAL1 deficiency induces a shift in metabolic gene expression profiles characterized by upregulation of glycolytic and lipogenic gene programs, together with suppression of genes linked to thermogenic and vascular homeostasis. Mechanistically, BMAL1 loss increased Mlxipl (encoding ChREBP) expression, and ChREBP knockdown attenuated the glycolytic\u2013lipogenic transcriptional response to BMAL1 depletion in cultured brown adipocytes. In parallel, BMAL1-deficient PVAT exhibited enlarged lipid droplets, increased oxidative stress-related transcriptional profile, and inflammatory remodeling accompanied by macrophage accumulation. In ApoE\u2212\/\u2212 mice, brown adipocyte-specific BMAL1 deletion aggravated atherosclerotic lesion formation in both chow-fed aging mice and Western diet-fed young mice, without major changes in systemic energy balance. In conclusion, brown adipocyte BMAL1 deficiency was associated with ChREBP-linked metabolic reprogramming, loss of brown-like PVAT features, oxidative and macrophage-associated remodeling, and increased atherosclerosis.<\/jats:p>","DOI":"10.3390\/cells15191791","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T08:19:08Z","timestamp":1790842748000},"page":"1791","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Brown Adipocyte BMAL1 Deficiency Is Associated with PVAT Remodeling and Increased Atherosclerosis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4992-8112","authenticated-orcid":false,"given":"Ruiyan","family":"Xu","sequence":"first","affiliation":[{"name":"Key Laboratory for Arteriosclerology of Hunan Province, Institute of Cardiovascular Disease, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Department of Pathophysiology, Hengyang Medical School, University of South China, Hengyang 421001, China"},{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenguo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenjuan","family":"Mu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3063-2167","authenticated-orcid":false,"given":"Yao","family":"Liu","sequence":"additional","affiliation":[{"name":"Key Laboratory for Arteriosclerology of Hunan Province, Institute of Cardiovascular Disease, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Department of Pathophysiology, Hengyang Medical School, University of South China, Hengyang 421001, China"},{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3334-9159","authenticated-orcid":false,"given":"Yanhong","family":"Guo","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jifeng","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Y Eugene","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guohua","family":"Li","sequence":"additional","affiliation":[{"name":"Key Laboratory for Arteriosclerology of Hunan Province, Institute of Cardiovascular Disease, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Department of Pathophysiology, Hengyang Medical School, University of South China, Hengyang 421001, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5621-8426","authenticated-orcid":false,"given":"Lin","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1038\/s41569-021-00668-4","article-title":"Therapeutic strategies targeting inflammation and immunity in atherosclerosis: How to proceed?","volume":"19","author":"Engelen","year":"2022","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1007\/s11883-025-01294-y","article-title":"The Atherosclerotic Plaque Microenvironment as a Therapeutic Target","volume":"27","author":"Pandit","year":"2025","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"817","DOI":"10.1038\/s41419-024-07166-8","article-title":"Inflammation in atherosclerosis: Pathophysiology and mechanisms","volume":"15","author":"Ajoolabady","year":"2024","journal-title":"Cell Death Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Han, Y., Xu, H., Yao, X., Li, Z., Zhu, C., Li, X., Chen, B., and Sun, H. (2025). Molecular mechanisms and therapeutic progress in atherosclerosis: Bridging immune inflammation and precision medicine. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1737662"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3827","DOI":"10.1093\/eurheartj\/ehad484","article-title":"Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers","volume":"44","author":"Antoniades","year":"2023","journal-title":"Eur. Heart J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1094","DOI":"10.1161\/ATVBAHA.120.312464","article-title":"Perivascular Adipose Tissue Regulates Vascular Function by Targeting Vascular Smooth Muscle Cells","volume":"40","author":"Chang","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Sowa, H., Karasaki, K., Ishiwata, M., Cheng, X., Hashimoto, M., and Ueda, K. (2026). Perivascular adipose tissue and vascular inflammation: From biological insights to clinical implications. Front. Physiol., 17.","DOI":"10.3389\/fphys.2026.1766197"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Zhang, S., Jiang, J., Luo, Y., Liu, G., Hu, S., Wan, S., Luo, C., Li, H., Li, N., and da Gra\u00e7a Esp\u00edrito Santo Vasconcelos, J. (2025). Molecular crosstalk in perivascular adipose tissue: Mechanisms of inflammation, metabolic dysregulation, and therapeutic opportunities in cardiovascular disease. Front. Cardiovasc. Med., 12.","DOI":"10.3389\/fcvm.2025.1613900"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1007\/s11883-025-01373-0","article-title":"Mechanistic Insight into PVAT Browning as a Protective Factor in Thoracic Aortic Aneurysm","volume":"28","author":"Mu","year":"2026","journal-title":"Curr. Atheroscler. Rep."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1186\/s12933-025-02814-5","article-title":"Vascular effects of perivascular adipose tissue-derived chemerin in obesity-associated cardiovascular disease","volume":"24","author":"Man","year":"2025","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Cai, M., Zhao, D., Han, X., Han, S., Zhang, W., Zang, Z., Gai, C., Rong, R., and Gao, T. (2023). The role of perivascular adipose tissue-secreted adipocytokines in cardiovascular disease. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1271051"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1186\/s12933-024-02549-9","article-title":"Perivascular adipose tissue: A central player in the triad of diabetes, obesity, and cardiovascular health","volume":"23","author":"Queiroz","year":"2024","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1738","DOI":"10.1161\/ATVBAHA.118.311367","article-title":"Brown Adipocyte-Specific PPARgamma (Peroxisome Proliferator-Activated Receptor gamma) Deletion Impairs Perivascular Adipose Tissue Development and Enhances Atherosclerosis in Mice","volume":"38","author":"Xiong","year":"2018","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1067","DOI":"10.1161\/CIRCULATIONAHA.112.104489","article-title":"Loss of perivascular adipose tissue on peroxisome proliferator-activated receptor-gamma deletion in smooth muscle cells impairs intravascular thermoregulation and enhances atherosclerosis","volume":"126","author":"Chang","year":"2012","journal-title":"Circulation"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"101979","DOI":"10.1016\/j.redox.2021.101979","article-title":"BMP4-mediated browning of perivascular adipose tissue governs an anti-inflammatory program and prevents atherosclerosis","volume":"43","author":"Mu","year":"2021","journal-title":"Redox Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"531","DOI":"10.1007\/s10557-018-6809-7","article-title":"MitoNEET in Perivascular Adipose Tissue Prevents Arterial Stiffness in Aging Mice","volume":"32","author":"Chang","year":"2018","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"107140","DOI":"10.1016\/j.phrs.2024.107140","article-title":"Perivascular fat tissue and vascular aging: A sword and a shield","volume":"203","author":"Wang","year":"2024","journal-title":"Pharmacol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"736","DOI":"10.1038\/s41589-025-01863-x","article-title":"Pharmacological targeting of BMAL1 modulates circadian and immune pathways","volume":"21","author":"Pu","year":"2025","journal-title":"Nat. Chem. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13578-022-00947-8","article-title":"Neural function of Bmal1: An overview","volume":"13","author":"Zheng","year":"2023","journal-title":"Cell Biosci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1038\/s41392-022-00899-y","article-title":"Molecular regulations of circadian rhythm and implications for physiology and diseases","volume":"7","author":"Fagiani","year":"2022","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1038\/s44323-025-00023-7","article-title":"Deletion of Arntl, a component of the molecular clock, in adipocytes leads to cellular hypertrophy by increasing insulin sensitivity via FGF21","volume":"2","author":"Ishii","year":"2025","journal-title":"npj Biol. Timing Sleep."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1161\/ATVBAHA.121.316480","article-title":"Clock Gene Bmal1 Disruption in Vascular Smooth Muscle Cells Worsens Carotid Atherosclerotic Lesions","volume":"42","author":"Lin","year":"2022","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1523","DOI":"10.1161\/ATVBAHA.120.314318","article-title":"Bmal1 Deletion in Myeloid Cells Attenuates Atherosclerotic Lesion Development and Restrains Abdominal Aortic Aneurysm Formation in Hyperlipidemic Mice","volume":"40","author":"Yang","year":"2020","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"101202","DOI":"10.1016\/j.molmet.2021.101202","article-title":"Brown adipocyte-specific knockout of Bmal1 causes mild but significant thermogenesis impairment in mice","volume":"49","author":"Hasan","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1161\/CIRCULATIONAHA.117.029972","article-title":"Bmal1 in Perivascular Adipose Tissue Regulates Resting-Phase Blood Pressure Through Transcriptional Regulation of Angiotensinogen","volume":"138","author":"Chang","year":"2018","journal-title":"Circulation"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"R960","DOI":"10.1152\/ajpregu.00128.2020","article-title":"Liver circadian clock disruption alters perivascular adipose tissue gene expression and aortic function in mice","volume":"320","author":"Pati","year":"2021","journal-title":"Am. J. Physiol. Regul. Integr. Comp. Physiol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"617","DOI":"10.1507\/endocrj.K07E-110","article-title":"ChREBP: A glucose-activated transcription factor involved in the development of metabolic syndrome","volume":"55","author":"Iizuka","year":"2008","journal-title":"Endocr. J."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Iizuka, K., Takao, K., and Yabe, D. (2020). ChREBP-Mediated Regulation of Lipid Metabolism: Involvement of the Gut Microbiota, Liver, and Adipose Tissue. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.587189"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"122843","DOI":"10.1016\/j.lfs.2024.122843","article-title":"ChREBP plays a pivotal role in the nutrient-mediated regulation of metabolic gene expression in brown adipose tissue","volume":"351","author":"Baek","year":"2024","journal-title":"Life Sci."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Hager, M., Adam, C., Mercier, L., Voorhees, A., Lee, M., Ball, L., Yang, J., Bartke, A., Miller, R.A., and Li, X. (2026). ChREBP-mediated regulation of lipid metabolism in liver and brown adipose tissue of long-lived mice. Geroscience, Epub ahead of print.","DOI":"10.1007\/s11357-026-02263-2"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1530\/JOE-19-0498","article-title":"ChREBP-beta regulates thermogenesis in brown adipose tissue","volume":"245","author":"Wei","year":"2020","journal-title":"J. Endocrinol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"A4140191","DOI":"10.1161\/circ.150.suppl_1.4140191","article-title":"ChREBP Drives Brown Adipocyte Differentiation and Lipid Utilization for Excess Energy Expenditure","volume":"150","author":"Inoue","year":"2024","journal-title":"Circulation"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1186\/s12933-024-02473-y","article-title":"Endothelial KLF11 is a novel protector against diabetic atherosclerosis","volume":"23","author":"Zhao","year":"2024","journal-title":"Cardiovasc. Diabetol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e158451","DOI":"10.1172\/JCI158451","article-title":"Metabolic changes in aging humans: Current evidence and therapeutic strategies","volume":"132","author":"Palmer","year":"2022","journal-title":"J. Clin. Investig."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1007\/s10522-025-10281-4","article-title":"Circadian clock and its effect on aging and lifespan","volume":"26","author":"Verma","year":"2025","journal-title":"Biogerontology"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"bqag023","DOI":"10.1210\/endocr\/bqag023","article-title":"Bmal1 regulates thermogenic function by modulation of lipolytic and oxidative phosphorylation gene expression in male mice brown adipocytes","volume":"167","author":"Nagata","year":"2026","journal-title":"Endocrinology"},{"key":"ref_37","first-page":"1835","article-title":"The adipocyte clock controls brown adipogenesis through the TGF-beta and BMP signaling pathways","volume":"128","author":"Nam","year":"2015","journal-title":"J. Cell Sci."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Carbinatti, T., Regnier, M., Parlati, L., Benhamed, F., and Postic, C. (2023). New insights into the inter-organ crosstalk mediated by ChREBP. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1095440"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"24029","DOI":"10.1074\/jbc.M801539200","article-title":"Glucose activates ChREBP by increasing its rate of nuclear entry and relieving repression of its transcriptional activity","volume":"283","author":"Davies","year":"2008","journal-title":"J. Biol. Chem."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1791\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:21:41Z","timestamp":1791951701000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/15\/19\/1791"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,30]]},"references-count":39,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2026,10]]}},"alternative-id":["cells15191791"],"URL":"https:\/\/doi.org\/10.3390\/cells15191791","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,30]]}}}