Gene Curbs Obesity by Reducing Inflammation, Aiding Healthy Gut Bacteria

Researchers at the University of North Carolina School of Medicine were on the trail of a protein that was linked to weight gain in mice when an ordinary safety precaution helped reveal what was happening: gut bacteria were at work.

The research, published in Cell Host & Microbe, concerns work on NLRP12, a gene that is produced in several types of immune cells and appears to function as a brake on excessive inflammation. Many studies have linked inflammation to obesity and diabetes; environmental factors including smoking, living in high crime areas, lack of sleep, or disrupted sleep from shift work have been cited as contributing factors in rising rates of these chronic conditions.

The authors of the North Carolina study have published studies that show mice lacking the NLRP12 gene are at risk of excessive inflammation, including colon inflammation and colon cancer. For this study, they fed mice lacking the NLRP12 gene, as well as ordinary mice, a high-fat diet for several months. The NLRP12-knockout mice ate and drank the same amount as the ordinary mice, but accumulated more fat, gained more weight, and showed more signs of insulin resistance.

In these mice, the accumulating fat led to signs of inflammation in the gut, but scientists couldn’t figure out why.

It happened that the scientists had to move some of the mice to another building, which required them to give the mice antibiotics to prevent the spread of disease. And that brought the discovery.

“We noticed that the mice treated with the antibiotics gained less weight than the mice that stayed in the old facility,” said study author Agnieszka Truax, PhD. “That led us to suspect gut bacteria were involved in promoting obesity.”

So the team did more tests with the NLRP12 mice in bacteria-free conditions and found that they did not gain weight. The “bad” bacteria had been fueling the weight gain, and the knockout mice were also somewhat protected from weight gain when housed with control mice because they had “good” gut bacteria.

The experiments revealed the following:

• Inflammation caused by a high-fat diet and made worse by the absence of NLRP12 was a major cause of the weight gain.
• When rival bacteria were killed off, that led to a rise in Erysipelotrichaceae, which promoted weight gain.
• By contrast, when researchers fed more beneficial bacteria to the knockout mice prior to and during the high-fat diet, it balanced out the gut bacteria, eliminating Erysipelotrichaceae and protecting the mice against obesity.

The “good” bacteria, called Lachnospiraceae, contain enzymes that convert carbohydrates and fiber into short-chain fatty acids, which have anti-inflammatory properties that promote gut health. Thus, the authors wrote, treating people with “good” bacteria or these fatty acids could offer a possible treatment for obesity or obesity-driven conditions.

Reference

Truax AD, Chen L, Tam JW, et al. The inhibitory innate immune sensor NLRP12 maintains a threshold against obesity by regulating gut microbiota homeostatis. Cell Host Microbe. 2018;24(3):364. doi: 10.1016/j.chom.2018.08.009.