The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis

Abstract

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-κB/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.

Canonical and noncanonical inflammasomes in intestinal epithelial cells

“…A similar increase in pro-inflammatory signalling in Nlrp12 −/− mice was recently shown in the context of HFD induced obesity (Truax et al, 2018). Notably, both untreated and HFD-fed Nlrp12 −/− mice harboured a dysbiotic microbiota and, in particular, a decrease in the enteroprotective Lachnospiraceae family (L. Chen et al, 2017;Truax et al, 2018). Although neither study was completely performed using littermate controls, in which wild type or knockout animals are generated for each experiment from a heterozygous parental cross, the results were repeatable using various breeding housing and germ-free reconstitution strategies across vivariums (L. Chen et al, 2017;Truax et al, 2018).…”

“…In comparison with nonlittermate Nlrp12 +/+ controls, Nlrp12 −/− mice display increased markers of NF‐κB pro‐inflammatory signalling and decreased survival when treated with DSS (Allen et al, ; L. Chen et al, ). A similar increase in pro‐inflammatory signalling in Nlrp12 −/− mice was recently shown in the context of HFD induced obesity (Truax et al, ). Notably, both untreated and HFD‐fed Nlrp12 −/− mice harboured a dysbiotic microbiota and, in particular, a decrease in the enteroprotective Lachnospiraceae family (L. Chen et al, ; Truax et al, ).…”

“…Chen et al, 2017). A similar increase in pro-inflammatory signalling in Nlrp12 −/− mice was recently shown in the context of HFD induced obesity (Truax et al, 2018). Notably, both untreated and HFD-fed Nlrp12 −/− mice harboured a dysbiotic microbiota and, in particular, a decrease in the enteroprotective Lachnospiraceae family (L. Chen et al, 2017;Truax et al, 2018).…”

“…Yet more recent in vitro studies demonstrate that NLRP12 in fact dampens NF‐κB signalling (Arthur, Lich, Aziz, Kotb, & Ting, ; Lich et al, ; Williams et al, ). Likewise, in vivo, NLRP12 has also been shown to negatively regulates NF‐κB signalling in response to a variety of stimuli including chemical models of colitis and high‐fat diet (HFD) induced obesity (Allen et al, ; L. Chen et al, ; Truax et al, ; Zaki et al, ) as well as during Salmonella typhimurium and Brucella abortus infection (Silveira et al, ; Zaki, Man, Vogel, Lamkanfi, & Kanneganti, ) but not during Klebsiella pneumonia or Mycobacterium tuberculosis infection or in response to stimulation with purified lipopolysaccharide (LPS; Allen et al, ). However, the role of other inflammasomes components in these latter studies remains unclear, and further studies are needed to examine whether regulation of NF‐κB by NLRP12 represent an inflammasome‐dependent or inflammasome‐independent function of the protein.…”

“…NLRP12 has also been implicated as a regulator of the intestinal microbiota (L. Chen et al, ; Truax et al, ). In comparison with nonlittermate Nlrp12 +/+ controls, Nlrp12 −/− mice display increased markers of NF‐κB pro‐inflammatory signalling and decreased survival when treated with DSS (Allen et al, ; L. Chen et al, ).…”