TY - JOUR
T1 - The Inhibitory Innate Immune Sensor NLRP12 Maintains a Threshold against Obesity by Regulating Gut Microbiota Homeostasis
AU - Truax, Agnieszka D.
AU - Chen, Liang
AU - Tam, Jason W.
AU - Cheng, Ning
AU - Guo, Hao
AU - Koblansky, A. Alicia
AU - Chou, Wei Chun
AU - Wilson, Justin E.
AU - Brickey, W. June
AU - Petrucelli, Alex
AU - Liu, Rongrong
AU - Cooper, Daniel E.
AU - Koenigsknecht, Mark J.
AU - Young, Vincent B.
AU - Netea, Mihai G.
AU - Stienstra, Rinke
AU - Sartor, R. Balfour
AU - Montgomery, Stephanie A.
AU - Coleman, Rosalind A.
AU - Ting, Jenny P.Y.
N1 - Funding Information:
We thank the UNC Center for Gastrointestinal Biology and Disease (CGIBD), the Microbiome Core Facility, the National Gnotobiotic Rodent Resource Center, and UNC Nutrition Obesity Research Center (supported by NIH P40 OD010995, P30-DK34987, and P30DK056350, and the Crohn’s and Colitis Foundation). This project is supported by NIH grants ( R01-CA156330 and R01-AI029564 to J.P.-Y.T., P01-DK094779 to J.P.-Y.T. and R.B.S., and T32-DK007737-19 and F-F32-DK098916-02 to A.D.T.), UNC-ITCMS grant ( T32-CA009156 to A.A.K. and J.W.T.), American Cancer Society ( PF-13-401-01 -TBE to J.E.W.), NMSS ( FG 1968-A-1 to W.-C.C.), NCI ( F99/K00 F99CA223019 to N.C.), ERC Consolidator grant (# 310372 to M.G.N.), Spinoza grant of the Netherlands Organization for Scientific Research, NIAID ( U19-AI067798 to W.J.B. and H.G.), and National Natural Science Foundation of China (# 81602494 to R.L.). The LCCC Animal Histopathology Core was supported in part by an NCI Center Core Support Grant ( CA016086 ).
Funding Information:
To investigate changes in the microbiota after cohousing, 16S rRNA gene sequencing analysis was performed on fecal DNA from SiHo or CoHo WT and Nlrp12 −/− mice fed HFD. Fecal samples from SiHo Nlrp12 −/− mice showed significantly reduced microbial diversity ( Figure 5 F) compared to SiHo WT and CoHo animals, which agreed with the heatmap of bacterial operational taxonomic units (OTUs) ( Figure 5 G). This is supported by PCA ( Figure 5 H) and the UniFrac distance metric ( Figure 5 I). Two-way ANOVA revealed an increased abundance of the Erysipelotrichaceae family but reduced Bacteroidales and Clostridiales orders and Lachnospiraceae family in the SiHo Nlrp12 −/− mice compared to SiHo WT mice. A comparison of cohoused Nlrp12 −/− and WT mice showed no difference in these bacteria ( Figure 5 J). These observations suggest a strong association of Erysipelotrichaceae with HFD-induced obesity in mice. Indeed, the abundance of Erysipelotrichaceae was negatively correlated with Clostridiales and Lachnospiraceae ( Figure 5 K), raising the possibility that these latter bacterial groups have the potential to reduce Erysipelotrichaceae and obesity. CoHo Nlrp12 −/− mice show attenuated nuclear p52, p-ERK, and IL1β compared to SiHo Nlrp12 −/− littermates ( Figure 5 L). These data indicate that the microbiota contribute to increased obesity, immune activation, and IL1β maturation in Nlrp12 −/− mice.
Funding Information:
We thank the UNC Center for Gastrointestinal Biology and Disease (CGIBD), the Microbiome Core Facility, the National Gnotobiotic Rodent Resource Center, and UNC Nutrition Obesity Research Center (supported by NIH P40 OD010995, P30-DK34987, and P30DK056350, and the Crohn's and Colitis Foundation). This project is supported by NIH grants (R01-CA156330 and R01-AI029564 to J.P.-Y.T., P01-DK094779 to J.P.-Y.T. and R.B.S., and T32-DK007737-19 and F-F32-DK098916-02 to A.D.T.), UNC-ITCMS grant (T32-CA009156 to A.A.K. and J.W.T.), American Cancer Society (PF-13-401-01-TBE to J.E.W.), NMSS (FG 1968-A-1 to W.-C.C.), NCI (F99/K00 F99CA223019 to N.C.), ERC Consolidator grant (#310372 to M.G.N.), Spinoza grant of the Netherlands Organization for Scientific Research, NIAID (U19-AI067798 to W.J.B. and H.G.), and National Natural Science Foundation of China (#81602494 to R.L.). The LCCC Animal Histopathology Core was supported in part by an NCI Center Core Support Grant (CA016086).
Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/9/12
Y1 - 2018/9/12
N2 - 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. Truax et al. show that myeloid-expressed NLRP12 restrains high-fat-diet-induced obesity and type 2 diabetes by attenuating TNF, IL-6, NF-kB, MAPK, M1-macrophage polarization, and inflammasome activation in adipose tissue. This protective function of NLRP12 is microbiota dependent, and is associated with Lachnospiraceae and their metabolites, which mitigate obesity.
AB - 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. Truax et al. show that myeloid-expressed NLRP12 restrains high-fat-diet-induced obesity and type 2 diabetes by attenuating TNF, IL-6, NF-kB, MAPK, M1-macrophage polarization, and inflammasome activation in adipose tissue. This protective function of NLRP12 is microbiota dependent, and is associated with Lachnospiraceae and their metabolites, which mitigate obesity.
KW - Erysipelotrichaceae
KW - Lachnospiraceae
KW - NLRP12
KW - inflammasome
KW - inflammation
KW - innate immunity
KW - microbiota
KW - obesity
KW - short-chain fatty acid
KW - type 2 diabetes
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U2 - 10.1016/j.chom.2018.08.009
DO - 10.1016/j.chom.2018.08.009
M3 - Article
C2 - 30212649
AN - SCOPUS:85052735485
SN - 1931-3128
VL - 24
SP - 364-378.e6
JO - Cell Host and Microbe
JF - Cell Host and Microbe
IS - 3
ER -