Body fat accumulation: a link between circadian rhythm and gut microbiota?

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Host metabolic pathways are synchronized with day–night cycles through the circadian clock. In mammals, this clock is a network containing various transcription factors including NFIL3, which is expressed in a variety of immune cells. More recently, it has also been found to be associated with intestinal epithelial cells (IECs).

A recently published study in Science from researchers at the University of Texas Southwestern (UT; TX, USA) has demonstrated that NFIL3 is expressed in small IECs. They also discovered that the gut microbiome appears to regulate lipid uptake and storage by altering the function of the circadian clock in these cells.

Lora Hooper (UT), the lead author of the study, commented: “These findings indicate a mechanism by which the intestinal microbiota regulate body composition and establish the circadian transcription factor NFIL3 as the essential molecular link among the microbiota, the circadian lock and host metabolism.”

Adding on to this, author Yuhao Wang (UT) explained: “The human gut is teeming with trillions of bacteria that help us digest our food, protect us from infection and produce certain vitamins. There is accumulating evidence that certain bacteria that live in our gut might predispose us to gain weight, especially when we consume a high fat, high sugar ‘Western-style’ diet.”

“Mice that lack a microbiome fare much better on a high-fat, Western-style diet than bacteria-bearing mice,” said Hooper.

In their experiments, the researchers investigated the physiological functions of NFIL3 in IECs by creating an Nfil3-knockout mouse and comparing it to germ-free and conventionally-raised mice when introduced to different diets.

Researchers uncovered that the gut microbiome regulated lipid uptake by ‘hacking’ into the circadian clocks present in IECs, in turn affecting how genes driving the lipid uptake and storage cycle were expressed. According to the scientists, this meant that germ-free mice lacking a microbiome produce less NFIL3. Consequently, this led to these mice storing less fat and remaining lean, even on a high-fat diet.

The body’s circadian clock functions by sensing day–night cycles. Although intestinal cells are not directly exposed to light, their circadian clocks receive light cues from the visual and nervous systems in order to regulate gene expression. Thus, the intestinal circadian clock helps to regulate NFIL3 expression and therefore the lipid metabolic machinery.

“So what you have is a really fascinating system where two signals from the environment come in – the microbiome and the day–night changes in light – and converge on the gut lining to regulate how much lipid you take up from your diet and store as fat,” Hooper remarked.

“Our work provides a deeper understanding of how the gut microbiota interacts with the circadian clock, and how this interaction impacts metabolism,” she continued. “It could also help to explain why people who work the night shift or travel abroad frequently – which disrupt their circadian clocks – have higher rates of metabolic diseases such as obesity, diabetes, and cardiovascular disease.”

Hooper cautioned that more research is required to determine if a similar mechanism regulates fat uptake in the human intestinal lining.

Sources: Wang Y, Kuang Z, Yu X et al. The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Science 357, 912–916 (2017); www.utsouthwestern.edu/newsroom/articles/year-2017/bacteria-clock-fat.html

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