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Protein links weight gain, biological clocks and gut microbes (2017-09-27)

Gut microbes “say” influences the activity of a key clock-driven protein called NFIL3, which can set intestinal cells up to absorb and store more fat from the diet while operating at hours that might run counter to our fixed biological clocks.

NFIL3 is a transcription factor, a protein that switches certain genes on and off.

Earlier studies had focused on its role in immune cells, but a team led by Lora Hooper at the University of Texas Southwestern Medical Center, Dallas, discovered that NFIL3 is also found in cells in the inner lining, or epithelium, of the mouse small intestine.

Intriguingly, as reported recently in the journal Science, they noticed that NFIL3 levels were much lower in the intestines of “germ-free” mice that don’t have any gut microbes.

IMAGE Caption: Lipids (red) inside mouse intestinal cells with and without NFIL3. Credit: Lora V. Hooper, University of Texas Southwestern Medical Center, Dallas

Hooper and colleagues generated mice that lacked the Nfil3 gene only in epithelial cells.
When those animals were raised on normal mouse chow, they grew leaner than their normal littermates.

When both groups were placed on a high-fat diet, the mice lacking NFIL3 in their intestines packed on a lot less weight.

They also had lower body fat and other indications of better health, including lower blood lipids, less fat in the liver, and fewer early signs of diabetes.

Many metabolic pathways are synchronized to day-and-night cycles that oscillate between greater activity during daylight and reduced activity at night.

Orchestrating this 24-hour cycle is a core network of transcription factors called the circadian clock that modulate the expression of numerous genes, including Nfil3, over the course of the day.

The circadian clock, however, doesn’t operate in isolation.
Recent studies suggest gut microbes interact with these transcription factors to affect metabolism profoundly.

The researchers established that the absence of gut microbes in germ-free mice caused NFIL3 levels to flatten out, losing the protein’s normal 24-hour rhythm and suggesting its expression is dependent on the microbes.

What might this mean for fat storage and weight gain?

For clues, the researchers delved deeper into the basic biology, comparing the activity of other genes in intestinal cells with and without NFIL3.

They uncovered differences in the activity of 33 genes, many of which follow a regular daily rhythm.

Seventeen of those genes were already known to encode proteins involved in the uptake of lipids or other aspects of metabolism.

It looked as though mice lacking NFIL3 might be leaner because their intestinal cells take up and store less fat from the diet.

To nail down this point, the researchers used a red stain to visualize lipids in the animals’ intestines.

As shown above, intestinal cells lacking NFIL3 contained much less lipid and the extra fat passed right on through the digestive systems of the mice.

Further studies showed gut microbes don’t talk directly to intestinal cells and NFIL3.

Rather, they go through an intermediary, sending messages to intestinal cells via the immune system.

Of course, these findings are in mice. But humans are known to have NFIL3, too, and further research will be needed to chase down this potentially important lead.

NFIL3 is a pleiotropic transcriptional regulator in both acquired and innate immunity. It has a critical role in T helper-2 (Th2) cytokine gene expression and controls IgE class switching and natural killer (NK) cell developmentNFIL3 is a pleiotropic transcriptional regulator in both acquired and innate immunity. It has a critical role in T helper-2 (Th2) cytokine gene expression and controls IgE class switching and natural killer (NK) cell development

OMIM® - Online Mendelian Inheritance in Man®
is a comprehensive, authoritative compendium of human genes and genetic phenotypes that is freely available and updated daily.
The full-text, referenced overviews in OMIM contain information on all known mendelian disorders and over 15,000 genes.
OMIM focuses on the relationship between phenotype and genotype. It is updated daily, and the entries contain copious links to other genetics resources

For more information
U.S. National Institutes of Health

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