CELL DEATH AND DIFFERENTIATION
·
2024
·
IF 13.7
Wang Shuai,He Ting,Luo Ya,Ren Kexin,Shen Huanming,Hou Lingfeng,Wei Yixin,Fu Tong,Xie Wenlong,Wang Peng,Hu Jie,Zhu Yu,Huang Zhengrong,Li Qiyuan,Li Weihua,Guo Huiling,Li Boan
Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors ( Sox4-MKO ) or brown adipocytes ( Sox4-BKO ) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of Sox4-MKO mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.
研究领域:
分子生物学
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细胞生物学
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代谢
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肥胖研究
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Journal of Biomedical Research
·
2022
·
IF 0
Mo-qiu Jia,Yong-jin Wang,Kang Fu,Han Jiao,Jia Sun,Yuanqing Gao
Orexin signaling has been associated with energy expenditure and brown adipose tissue (BAT) function. However, conflicting data exist in the field about how orexin signaling regulates BAT thermogenesis. In this study, we show that a specific orexin receptor type 2 (OX2R) agonist [Ala11, D-Leu15]-OxB (OB-Ala) inhibited intrascapular brown adipose tissue (iBAT) thermogenesis by reducing sympathetic output to iBAT. This effect is mediated by OX2Rs located on afferent nerve endings innervating iBAT instead of brown adipocyte itself. Microinjection of OB-Ala into iBAT inhibited iBAT thermogenesis in mice upon cold exposure and neuronal activity in the paraventricular nucleus. Findings suggest that OB-Ala could inhibit iBAT thermogenesis by attenuating sensory input thereby inhibiting the sympathetic-sensory iBAT feedback loop. Our study uncovers a novel primary action site of orexin in the regulation of energy balance.
研究领域:
神经科学
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内分泌学
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代谢
✓ 已验证
产品关联
DOI
PubMed
Nature Communications
·
2023
·Vol. 14
·期 1
·1-17
·
IF 16.6
Xiao Fei,Jiang Haizhou,Li Zi,Jiang Xiaoxue,Chen Shanghai,Niu Yuguo,Yin Hanrui,Shu Yousheng,Peng Bo,Lu Wei,Li Xiaoying,Li Zhigang,Lan Shujue,Xu Xiaoyan,Guo Feifan
An important role for liver in the regulation of adipose tissue thermogenesis upon cold exposure has been suggested; however, the underlying mechanisms remain incompletely defined. Here, we identify elevated serum bradykinin levels in response to acute cold exposure in male mice. A bolus of anti-bradykinin antibodies reduces body temperature during acute cold exposure, whereas bradykinin has the opposite effect. We demonstrate that bradykinin induces brown adipose tissue thermogenesis and white adipose tissue browning, and bradykinin increases uncoupling protein 1 (UCP1) expression in adipose tissue. The bradykinin B2 receptor (B2R), adrenergic signaling and nitric oxide signaling are involved in regulating bradykinin-increased UCP1 expression. Moreover, acute cold exposure inhibits hepatic prolyl endopeptidase (PREP) activity, causing reduced liver bradykinin degradation and increased serum bradykinin levels. Finally, by blocking the breakdown of bradykinin, angiotensin-converting enzyme inhibitors (ACEIs) increase serum bradykinin levels and induce brown adipose tissue thermogenesis and white adipose tissue browning via B2R. Collectively, our data provide new insights into the mechanisms underlying organ crosstalk in whole-body physiology control during cold exposure and also suggest bradykinin as a possible anti-obesity target.
研究领域:
生理学
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内分泌学
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代谢
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
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