Brown Adipocyte BMAL1 Deficiency Is Associated with PVAT Remodeling and Increased Atherosclerosis
- 1Key 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
- 2Department of Internal Medicine, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, MI 48105, USA
Abstract
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–lipogenic 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−/− 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.
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BibTeX
@article{xu2026brown,
title = {{Brown Adipocyte BMAL1 Deficiency Is Associated with PVAT Remodeling and Increased Atherosclerosis}},
author = {Ruiyan Xu and Zhenguo Wang and Wenjuan Mu and Juan Zhong and Yao Liu and Yanhong Guo and Jifeng Zhang and Y Eugene Chen and Guohua Li and Lin Chang},
journal = {Cells},
year = {2026},
month = sep,
doi = {10.3390/cells15191791},
url = {https://www.mdpi.com/2073-4409/15/19/1791},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Brown Adipocyte BMAL1 Deficiency Is Associated with PVAT Remodeling and Increased Atherosclerosis
AU - Ruiyan Xu
AU - Zhenguo Wang
AU - Wenjuan Mu
AU - Juan Zhong
AU - Yao Liu
AU - Yanhong Guo
AU - Jifeng Zhang
AU - Y Eugene Chen
AU - Guohua Li
AU - Lin Chang
PY - 2026
DA - 2026/09/30
JO - Cells
DO - 10.3390/cells15191791
UR - https://www.mdpi.com/2073-4409/15/19/1791
AB - 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–lipogenic 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−/− 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.
SN - 2073-4409
ER -