The clock-modulatory activity of Nobiletin suppresses adipogenesis via Wnt signaling.
The clock-modulatory activity of Nobiletin suppresses adipogenesis via Wnt signaling.
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Nobiletin 的时钟调节活性通过 Wnt 信号传导抑制脂肪生成。
DOI：
10.1101/2023.02.07.527587
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Ma,Ke
中科院分区：
文献类型：
--
作者：
Xiong,Xuekai;Kiperman,Tali;Li,Weini;Dhawan,Sangeeta;Lee,Jeongkyung;Yechoor,Vijay;Ma,Ke
生物钟机制发挥转录调控作用来调节脂肪形成，其破坏导致肥胖的发展。在这里，我们报告Nobiletin，一种生物钟振幅增强分子，通过激活依赖于其时钟调节的Wnt信号通路显示抗脂肪形成特性。Nobiletin增强了成脂间充质前体细胞和前脂肪细胞的时钟振荡幅度，并伴随着负反馈臂内Bmal 1和时钟成分的诱导。与其时钟调节活性一致，Nobiletin强烈抑制成脂祖细胞的谱系定型和终末分化。从机制上讲，我们发现Nobiletin通过转录上调该途径中的关键组分，诱导脂肪形成过程中Wnt信号的重新激活。此外，Nobiletin给药小鼠显著减少脂肪细胞肥大，导致脂肪量显著减少和体重减轻。最后，Nobiletin抑制原代前脂肪细胞的分化，这种作用依赖于功能性时钟调节。总的来说，我们的研究结果揭示了Nobiletin以时钟依赖性方式抑制脂肪细胞发育的新活性，暗示其在对抗肥胖和相关代谢后果中的潜在应用。
The circadian clock machinery exerts transcriptional control to modulate adipogenesis and its disruption leads to the development of obesity. Here, we report that Nobiletin, a circadian clock amplitude-enhancing molecule, displays antiadipogenic properties via activation of Wnt signaling pathway that is dependent on its clock modulation. Nobiletin augmented clock oscillatory amplitude with period lengthening in the adipogenic mesenchymal precursor cells and preadipocytes, accompanied by an induction of Bmal1 and clock components within the negative feedback arm. Consistent with its clock-modulatory activity, Nobiletin strongly inhibited the lineage commitment and terminal differentiation of adipogenic progenitors. Mechanistically, we show that Nobiletin induced the reactivation of Wnt signaling during adipogenesis via transcriptional up-regulation of key components within this pathway. Furthermore, Nobiletin administration in mice markedly reduced adipocyte hypertrophy, leading to a significant loss of fat mass and reduction of body weight. Last, Nobiletin inhibited the differentiation of primary preadipocytes, and this effect was dependent on a functional clock regulation. Collectively, our findings uncover a novel activity of Nobiletin in suppressing adipocyte development in a clock-dependent manner, implicating its potential application in countering obesity and associated metabolic consequences.
影响因子：
29
作者：
Hatori M;Vollmers C;Zarrinpar A;DiTacchio L;Bushong EA;Gill S;Leblanc M;Chaix A;Joens M;Fitzpatrick JA;Ellisman MH;Panda S
通讯作者：
Panda S
训练昼夜节律时钟，对药物进行时钟，并为时钟吸毒以预防，管理和治疗慢性疾病。
影响因子：
13.8
作者：
Sulli G;Manoogian ENC;Taub PR;Panda S
通讯作者：
Panda S