Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction

Abstract

Genetics plays a central role in susceptibility to obesity and metabolic diseases. BALB/c mice are known to be resistant to high fat diet (HFD)-induced obesity, however the genetic cause remains unknown. We report that deletion of the innate immunity antibacterial gene Nod2 abolishes this resistance, as Nod2 −/− BALB/c mice developed HFD-dependent obesity and hallmark features of metabolic syndrome. Nod2 −/− HFD mice developed hyperlipidemia, hyperglycemia, glucose intolerance, increased adiposity, and steatosis, with large lipid droplets in their hepatocytes. These changes were accompanied by increased expression of immune genes in adipose tissue and differential expression of genes for lipid metabolism, signaling, stress, transport, cell cycle, and development in both adipose tissue and liver. Nod2 −/− HFD mice exhibited changes in the composition of the gut microbiota and long-term treatment with antibiotics abolished diet-dependent weight gain in Nod2 −/− mice, but not in wild type mice. Furthermore, microbiota from Nod2 −/− HFD mice transferred sensitivity to weight gain, steatosis, and hyperglycemia to wild type germ free mice. In summary, we have identified a novel role for Nod2 in obesity and demonstrate that Nod2 and Nod2-regulated microbiota protect BALB/c mice from diet-induced obesity and metabolic dysfunction.

Combined analysis of whole‐exon sequencing and lncRNA sequencing in type 2 diabetes mellitus patients with obesity

“…Previous studies have shown that NOD2 mediates activation of the NF‐kBT transcriptional regulator family in response to different peptidoglycan fragments and that NOD2 can contribute to host defence by promoting the production of pro‐inflammatory cytokines and antimicrobial molecules . Deletion of the NOD2 gene abolished the resistance of BALA/C mice to HFD‐induced obesity, and the same phenomenon was observed in C57BL/6 mice . In line with previous studies, in this study, we found that the NOD2 gene showed missense mutations at the rs104895427 and rs5743277 sites in the exonic region of O‐T2DM patients compared with healthy subjects, and it also showed a significant down‐regulation in mRNA expression levels (log2fold‐change = −0.986).…”

Of genes and microbes: solving the intricacies in host genomes

“…coli mpk / B . vulgatus IBD Bohn et al ( 2006 ) Nlrp12 Gut microbiome composition IBD Chen et al ( 2017a , b ) Sirt1 Gut microbiome composition IBD, colorectal cancer Lo Sasso et al ( 2014 ) Muc2 Gut microbiome composition Ileal homeostasis Sovran et al ( 2015 ) Mhc Gut microbiome composition Immunology Kubinak et al ( 2015a , b ) B4galnt2 Gut microbiome composition and Salmonella susceptibility Inflammation Rausch et al ( 2015 ) TREM-1 General dysbiosis in gut microbiome Inflammation Kökten et al ( 2018 ) Nod2 Gut microbiome under high fat diet Obesity Rodriguez-Nunez et al ( 2017 ) Fut2 Multi-generation dynamics of gut microbiome Susceptibility to enteric infection Rausch et al ( 2017 ) …”

NOD2 and inflammation: current insights

“…Recent literature describes a central role of NOD2 in susceptibility to obesity and metabolic dysfunction. 139 NOD2 -deficient mice show increased bacterial adherence to the intestinal mucosa and bacterial infiltration in metabolic tissues, such as hepatic and adipose tissue, exacerbating inflammation and insulin resistance. 140 Moreover, NOD2−/− BALB/c mice have shown susceptibility to obesity, hyperlipidemia, hyperglycemia, glucose intolerance, increased adiposity and hepatic steatosis, as compared to WT mice.…”