Institute of Molecular Rhythm and Metabolism, Guangzhou University of Chinese Medicine, Guangzhou, China.
College of Pharmacy, Jinan University, Guangzhou, China.
Nat Commun. 2021 Sep 7;12(1):5323. doi: 10.1038/s41467-021-25674-5.
The role of intestine clock in energy homeostasis remains elusive. Here we show that mice with Bmal1 specifically deleted in the intestine (Bmal1 mice) have a normal phenotype on a chow diet. However, on a high-fat diet (HFD), Bmal1 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.
肠道时钟在能量平衡中的作用仍然难以捉摸。在这里，我们发现肠道中特异性缺失 Bmal1 的小鼠（Bmal1 小鼠）在正常饮食下表现正常。然而，在高脂肪饮食（HFD）下，Bmal1 小鼠可以防止肥胖及其相关异常的发生，如高血脂和脂肪肝。这些代谢表型归因于肠道中脂质合成受损和脂肪分泌减少。一致地，在夜间（BMAL1 表达较低）给予 HFD 的野生型小鼠与自由进食的小鼠相比，肥胖程度减轻。机制研究揭示了 BMAL1 通过直接结合启动子中的 E-box 来反式激活 Dgat2 基因（编码三酰基甘油合成酶 DGAT2），从而促进膳食脂肪吸收。支持这些发现，肠道中 Rev-erbα（已知的 BMAL1 抑制剂）的缺乏会增强膳食脂肪吸收，并加剧 HFD 诱导的肥胖和合并症。此外，通过小分子靶向 REV-ERBα/BMAL1 来治疗 SR9009 可以改善 HFD 诱导的肥胖。总之，肠道时钟作为膳食脂肪吸收的加速器，靶向肠道 BMAL1 可能是管理过量脂肪摄入引起的代谢性疾病的一种有前途的方法。
