A study from the UNC School of Medicine showed that the protein NLRP12, known for its anti-inflammatory effects, also protects mice on a high-fat diet against obesity and insulin resistance; it might have a similar effect in humans .
In addition to high-fat diet (HFD) and inactivity, inflammation and microbiota composition contribute to obesity. Inhibitory immune receptors, such as NLRP12, dampen inflammation and are important for resolving inflammation, but their role in obesity is unknown. We show that obesity in humans correlates with reduced expression of adipose tissue NLRP12. Similarly, Nlrp12/ mice show increased weight gain, adipose deposition, blood glucose, NF-kB/ MAPK activation, and M1-macrophage polarization. Additionally, NLRP12 is required to mitigate HFD-induced inflammasome activation. Co-housing with wild-type animals, antibiotic treatment, or germ-free condition was sufficient to restrain inflammation, obesity, and insulin tolerance in Nlrp12/ mice, implicating the microbiota. HFD-fed Nlrp12/ mice display dysbiosis marked by increased obesity-associated Erysipelotrichaceae, but reduced Lachnospiraceae family and the associated enzymes required for short-chain fatty acid (SCFA) synthesis. Lachnospiraceae or SCFA administration attenuates obesity, inflammation, and dysbiosis. These findings reveal that Nlrp12 reduces HFD-induced obesity by maintaining beneficial microbiota.
Obesity, inflammation, and disease
Obesity, or simply being overweight, presents challenges per se, but it is also a significant risk factor for multiple diseases, including stroke, cancer, and diabetes.
While a sedentary lifestyle and an unhealthy diet are certainly drivers of obesity, inflammation plays a role as well. Research increasingly points out the existence of a connection between obesity and inflammation of fat deposits and the gut, and there is also a connection between obesity and gut microbiota imbalance; indeed, higher numbers of certain gut bacteria are linked to higher inflammation, while the presence of other, “good” bacteria mitigates inflammation.
This study showed that the protein NLRP12, encoded by the homonymous gene, promotes the growth of certain “good” bacteria known as Lachnospiraceae—a family of bacteria that digests carbs and fibers, producing butyrate and propionate in the process; we discussed the benefits of butyrate in a previous article about a study on its anti-inflammatory effects on the guts and brains of older mice.
Both NLRP12-knockout and control mice were fed the same high-fat diet over the course of several months. The most immediate, visible effect was that the NLRP12 knockouts became fatter and heavier than the controls despite the identical diet, and they also developed insulin resistance—a reduced ability to clear up blood glucose that tends to accompany obesity. The NLRP12 knockouts also displayed higher inflammation levels in their guts and fat deposits compared to the controls. This suggested that, indeed, the NLRP12 protein somehow protected against obesity, though it wasn’t clear how. As the researchers moved some test mice to another lab facility, they administered them a round of antibiotics as part of standard safety procedures, which serendipitously revealed the link.
Mice dosed with antibiotics gained less weight than did the NLRP12 knockouts that remained at the older facility and weren’t administered the drugs; as antibiotics wipe out the gut microbiome, the researchers began to think that, perhaps, it might play a role in weight gain. Indeed, in a subsequent experiment, NLRP12 knockouts kept in an aseptic environment didn’t gain any weight, despite the high-fat diet and the lack of NLRP12.
At this point, “bad” bacteria appeared to have been the culprit all along. It has been known for a while that high-fat diets may reduce gut microbiome diversity, promoting the growth of “bad”, inflammation-inducing bacteria (specifically, the Erysipelotrichaceae family) over “good” ones (the aforementioned Lachnospiraceae). NLRP12 knockouts were worse off than controls because the lack of this anti-inflammatory protein drove inflammation even further; however, wiping their gut microbiome via antibiotics purged the inflammation-inducing bacteria as well, thereby eliminating a major driving factor of the problem. Interestingly, the researchers observed that co-housing NLRP12 knockouts with controls also helped the former stay in better shape; this suggests that “good” bacteria from the controls spread to the knockouts and improved their health.
The benefits of Lachnospiraceae bacteria were confirmed when the researchers administered them to NLRP12 knockouts—both before and during the high-fat diet—and observed that gut inflammation was driven down as well as the Erysipelotrichaceae population; obesity and insulin resistance were also significantly reduced.
Lachnospiraceae bacteria tend to produce abundant short-chain fatty acids, particularly butyrate and propionate, which are known for their anti-inflammatory properties and their benefits to gut health; as the researchers found out, feeding these compounds to NLRP12 knockouts produced the same benefits as the presence of Lachnospiraceae in the same circumstances.
The takeaway from this study appears to be that pro-inflammatory diets are a bad idea, especially for obese patients, in whom expression levels of NLRP12 are lower than in healthy people; however, it is possible that administering Lachnospiraceae, or butyrate and propionate, might turn out to be a viable, future strategy to counter obesity and the many conditions it drives.
Additionally, it is looking ever more likely that age-related changes to the gut microbiome and the decline of beneficial butyrate-producing bacteria also contributes significantly to an aging process, which we discuss in a related article. This study further supports that the gut microbiome plays an important role in metabolism, immune system function, inflammation, and aging.
 Truax, A. D., Chen, L., Tam, J. W., Cheng, N., Guo, H., Koblansky, A. A., … Ting, J. P.-Y. (2018). The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis. Cell Host & Microbe, 24(3), 364–378.e6.