Deficiency of intestinal Bmal1 prevents obesity induced by high-fat feeding.
Deficiency of intestinal Bmal1 prevents obesity induced by high-fat feeding.
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肠道 Bmal1 缺乏可预防高脂喂养引起的肥胖
DOI：
10.1038/s41467-021-25674-5
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发表时间：
2021-09-07
影响因子：
16.6
通讯作者：
Wu B
中科院分区：
文献类型：
--
作者：
Yu F;Wang Z;Zhang T;Chen X;Xu H;Wang F;Guo L;Chen M;Liu K;Wu B
肠道生物钟在能量平衡中的作用仍然是难以捉摸的。在这里，我们表明，在肠道中特异性缺失Bmal 1的小鼠（Bmal 1 iKO小鼠）在普通饮食中具有正常的表型。然而，在高脂肪饮食（HFD）中，Bmal 1 iKO小鼠被保护免于肥胖和相关异常（例如高脂血症和脂肪肝）的发展。这些代谢表型归因于肠内脂质再合成受损和脂肪分泌减少。一致地，与随意喂食的小鼠相比，在夜间喂食HFD的野生型小鼠（具有较低的BMAL 1表达）显示减轻的肥胖。机制研究发现，BMAL 1通过直接结合启动子中的E-box反式激活Dgat 2基因（编码三酰甘油合成酶DGAT 2），从而促进膳食脂肪吸收。支持这些发现的是，肠内Rev-erbα（一种已知的BMAL 1阻遏物）缺乏可增强膳食脂肪吸收，并加剧HFD诱导的肥胖和合并症。此外，SR9009对REV-ERBα/BMAL 1的小分子靶向作用可改善HFD诱导的小鼠肥胖。总之，肠道生物钟作为膳食脂肪吸收的加速剂，靶向肠道BMAL 1可能是管理过量脂肪摄入引起的代谢疾病的一种有前途的方法。组织生物钟有助于生理和代谢的调节。在这里，作者研究了肠道生物钟在能量稳态中的作用，并表明肠道生物钟在膳食脂肪吸收中起着加速剂的作用。
The role of intestine clock in energy homeostasis remains elusive. Here we show that mice with Bmal1 specifically deleted in the intestine (Bmal1iKO mice) have a normal phenotype on a chow diet. However, on a high-fat diet (HFD), Bmal1iKO mice are protected against development of obesity and related abnormalities such as hyperlipidemia and fatty livers. These metabolic phenotypes are attributed to impaired lipid resynthesis in the intestine and reduced fat secretion. Consistently, wild-type mice fed a HFD during nighttime (with a lower BMAL1 expression) show alleviated obesity compared to mice fed ad libitum. Mechanistic studies uncover that BMAL1 transactivates the Dgat2 gene (encoding the triacylglycerol synthesis enzyme DGAT2) via direct binding to an E-box in the promoter, thereby promoting dietary fat absorption. Supporting these findings, intestinal deficiency of Rev-erbα, a known BMAL1 repressor, enhances dietary fat absorption and exacerbates HFD-induced obesity and comorbidities. Moreover, small-molecule targeting of REV-ERBα/BMAL1 by SR9009 ameliorates HFD-induced obesity in mice. Altogether, intestine clock functions as an accelerator in dietary fat absorption and targeting intestinal BMAL1 may be a promising approach for management of metabolic diseases induced by excess fat intake. Tissue circadian clocks contribute to the regulation of physiology and metabolism. Here the authors investigate the role of the intestinal circadian clock in energy homeostasis and show that the intestinal clock acts as an accelerator in dietary fat absorption.
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影响因子：
5.9
作者：
Müller M;Canfora EE;Blaak EE
通讯作者：
Blaak EE
影响因子：
4.4
作者：
Keleher, Madeline Rose;Zaidi, Rabab;Cheverud, James M.
通讯作者：
Cheverud, James M.
影响因子：
6.5
作者：
Ables GP;Yang KJ;Vogel S;Hernandez-Ono A;Yu S;Yuen JJ;Birtles S;Buckett LK;Turnbull AV;Goldberg IJ;Blaner WS;Huang LS;Ginsberg HN
通讯作者：
Ginsberg HN
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
影响因子：
15.9
作者：
KAYDEN, HJ;SENIOR, JR;MATTSON, FH
通讯作者：
MATTSON, FH