Protein Links Gut Microbes, Biological Clocks, and Weight Gain
Posted on by Dr. Francis Collins
The American epidemic of obesity is a major public health concern, and keeping off the extra pounds is a concern for many of us. Yet it can also be a real challenge for people who may eat normally but get their days and nights mixed up, including night-shift workers and those who regularly travel overseas. Why is that?
The most obvious reason is the odd hours throw a person’s 24-hour biological clock—and metabolism—out of sync. But an NIH-funded team of researchers has new evidence in mice to suggest the answer could go deeper to include the trillions of microbes that live in our guts—and, more specifically, the way they “talk” to intestinal cells. Their studies suggest that what 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. That information suggested that the NFIL3 transcription factor responds to gut microbes, and raised an obvious question: What else does NFIL3 do in intestinal cells?
To find out, 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.
This brought them somewhat unexpectedly to the fascinating area of circadian biology. 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 . That’s why it was interesting when the researchers followed up and 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. In other words, it’s complicated. But based on their work, the researchers say NFIL3 seems to be “an essential molecular link” among the circadian clock, microbes, and metabolism.
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. If confirmed, it could offer new clues as to why some people are leaner than others, and might suggest new ways of preventing or treating an array of metabolic conditions, including obesity, diabetes, and heart disease.
 The intestinal microbiota regulates body composition through NFIL3 and the circadian clock. Wang Y, Kuang Z, Yu X, Ruhn KA, Kubo M, Hooper LV. Science. 2017 Sep 1;357(6354):912-916.
 Antagonistic role of E4BP4 and PAR proteins in the circadian oscillatory mechanism. Mitsui S, Yamaguchi S, Matsuo T, Ishida Y, Okamura H. Genes Dev. 2001 Apr 15;15(8):995-1006.
 Transkingdom control of microbiota diurnal oscillations promotes metabolic homeostasis. Thaiss CA, Zeevi D, Levy M, Zilberman-Schapira G, Suez J, Tengeler AC, Abramson L, Katz MN, Korem T, Zmora N, Kuperman Y, Biton I, Gilad S, Harmelin A, Shapiro H, Halpern Z, Segal E, Elinav E. Cell. 2014 Oct 23;159(3):514-529.
Understanding Adult Overweight and Obesity (National Institute of Diabetes and Digestive and Kidney Diseases/NIH)
Hooper Lab (University of Texas Southwestern Medical Center, Dallas)
NIH Support: National Institute of Diabetes and Digestive and Kidney Diseases
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Tags: biological clock, blood lipids, circadian biology, circadian clock, diabetes, fat, gut microbiome, gut-dwelling microbes, intestine, lipids, metabolism, microbiome, microbiota, NFIL3, night shift workers, obesity, overseas travel, small intestine, transcription factors, travel, weight gain
Obesity is a hand to mouth disease. No labels for calories in wine, beer, hard spirits. 1/5th of 100 proof Vodka = 2,400 Kcalories. Fructose is toxic, kill livers, causes insulin resistance. Collins misses the targets and look at mice. We published a controlled diet study in our metabolic unit, Am J of Clinical Nutrition, Effect of diet composition on metabolic adaptations to hypocaloric nutrition: comparison of high carbohydrate and high fat isocaloric diets, Lewis, Wallin, Kane and Gerich, AJCN 30: 1977 pp 160-170. 10 Kcal/Kg of body weight 70% fat vs 70% carbohydrate led to the same weight loss of a pound a day. Zero fat diets switching to the Mediterranean Diet works. The sleeve gastrectomy works when all else fails. Remember a BMI >26 Kg/meters squared made me deny life insurance under Navy Mutual Aid guideline. Overweight and obesity KILLS.
I believe this is a wonderful study, and very promising. It makes a lot sense the fact of how a germ rich intestinal environment, leads to abundant levels of NFIL3 and the subjects of experimentation to gain significantly more weight than the subjects with an intestinal germ-free environment and lower NFIL3 levels.
Now that the potential source of the origin of weight gain may have been identified, a clinical study with humans is needed to compare and verify if equivalent results are obtained. This may be the beginning of finding an additional, aggressive and viable way to inhibit or reduce levels of NFIL3 and to fight obesity.
Please forgive my ignorance but paragraph 5 says:
“To find out, 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.”
The first line says:
“Hooper and colleagues generated mice that lacked the Nfil3 gene.
Would it be more proper to say HIF3 A?
Thanks for your comment. Did you mean NFIL3 rather than HIF3? I’m not sure that I follow your question.
That’s the reason I love science. Everyday new things with so much details. Definitely I want to look lean and would love to see more on it.
Well that should solve the issue of why I am a bit obsessed than my brother when we eat the same food served.
i’m gaining weight day by day does it only the reason for that?
I eat very heavy protein foods but not gaining weight
Nice writing, Thanks for sharing this.
Obesity, diabetic, and even hypertension are mainly caused by lacking of hunger in modern life. Between 40-50, I was overweight, and had hypertension. Intermittent fasting not only reduced my weight, but also returned my blood pressure to normal in the last three years. The educational effort in this direction will be more cost-efficient than developing another lean drug.