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.
Highlights
The role of intestine clock in energy homeostasis remains elusive
Intestinal fat absorption is a multistep process: dietary TAGs are first hydrolyzed in intestinal lumen to free fatty acids (FFAs) and monoacylglycerols (MAGs) which are subsequently taken up by the enterocytes, followed by resynthesis of TAGs in the cells and TAG packaging into chylomicrons for secretion to the circulation[1,2]
In the MAG pathway, MAGs are re-esterified with an FFA to form diacylglycerols (DAGs) by the enzymes monoacylglycerol acyltransferases (MOGATs), and DAGs are further esterified by diacylglycerol acyltransferases (DGATs) to produce TAGs
Summary
The role of intestine clock in energy homeostasis remains elusive. Here we show that mice with Bmal[1] deleted in the intestine (Bmal1iKO mice) have a normal phenotype on a chow diet. 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. Mechanistic studies uncover that BMAL1 transactivates the Dgat[2] 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. Circadian variations in fat absorption and other intestinal activities (e.g., DNA synthesis, cell proliferation, gastric and colonic motilities) have been noted, the precise role of the intestine clock in fat absorption and obesity development remains poorly defined and the underlying mechanisms are unaddressed[19,20]. To investigate the functional relevance of the intestine clock in dietary fat absorption and energy homeostasis, it is necessary to generate and test the mouse lines with intestine-specific deletion of the core clock gene
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