Deficiency of intestinal Bmal1 prevents obesity induced by high-fat feeding

Fangjun Yu, Zhigang Wang, Tianpeng Zhang, Xun Chen, Haiman Xu, Fei Wang, Lianxia Guo, Min Chen, Kaisheng Liu () and Baojian Wu ()
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Fangjun Yu: Guangzhou University of Chinese Medicine
Zhigang Wang: First Affiliated Hospital of Jinan University
Tianpeng Zhang: Guangzhou University of Chinese Medicine
Xun Chen: Jinan University
Haiman Xu: Jinan University
Fei Wang: Jinan University
Lianxia Guo: Jinan University
Min Chen: Jinan University
Kaisheng Liu: The Second Clinical Medical College of Jinan University
Baojian Wu: Guangzhou University of Chinese Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-25674-5

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