Loss of Nlrp3 Does Not Protect Mice from Western Diet-Induced Adipose Tissue Inflammation and Glucose Intolerance

Abstract

We tested the hypothesis that loss of Nlrp3 would protect mice from Western diet-induced adipose tissue (AT) inflammation and associated glucose intolerance and cardiovascular complications. Five-week old C57BL6J wild-type (WT) and Nlrp3 knockout (Nlrp3-/-) mice were randomized to either a control diet (10% kcal from fat) or Western diet (45% kcal from fat and 1% cholesterol) for 24 weeks (n = 8/group). Contrary to our hypothesis that obesity-mediated white AT inflammation is Nlrp3-dependent, we found that Western diet-induced expression of AT inflammatory markers (i.e., Cd68, Cd11c, Emr1, Itgam, Lgals, Il18, Mcp1, Tnf, Ccr2, Ccl5 mRNAs, and Mac-2 protein) were not accompanied by increased caspase-1 cleavage, a hallmark feature of NLRP3 inflammasome activation. Furthermore, Nlrp3 null mice were not protected from Western diet-induced white or brown AT inflammation. Although Western diet promoted glucose intolerance in both WT and Nlrp3-/- mice, Nlrp3-/- mice were protected from Western diet-induced aortic stiffening. Additionally, Nlrp3-/- mice exhibited smaller cardiomyocytes and reduced cardiac fibrosis, independent of diet. Collectively, these findings suggest that presence of the Nlrp3 gene is not required for Western diet-induced AT inflammation and/or glucose intolerance; yet Nlrp3 appears to play a role in potentiating arterial stiffening, cardiac hypertrophy and fibrosis.

Lack of NLRP3-inflammasome leads to gut-liver axis derangement, gut dysbiosis and a worsened phenotype in a mouse model of NAFLD

“…Activation of inflammasome components has been shown in patients with chronic hepatic injury, particularly NASH, and in experimental models of NAFLD 21 , 23 . However, lack of NLRP3 was associated with reduced steatosis in some studies but it had no effects in others 21 , 46 – 48 . In the choline-deficient L-amino acid-defined (CDAA) model of liver injury, although not associated with features of the metabolic syndrome, inflammasome activation occurred during steatohepatitis development, whereas Nlrp3 −/− mice were protected during CDAA treatment 22 , 23 .…”

Soy Improves Cardiometabolic Health and Cecal Microbiota in Female Low-Fit Rats

“…It should be noted that only gene expression was measured in the present study, and the up-regulated inflammatory genes were not validated with protein measures. Although we have previously shown strong correlations between WAT inflammatory gene and protein expression 45 , future studies should measure inflammatory proteins to validate the inflammatory changes observed here.…”

Fish Oil Derived Omega 3 Fatty Acids Suppress Adipose NLRP3 Inflammasome Signaling in Human Obesity

“…Expression of NRLP3 components have been found to be increased in adipose tissue of obese humans and mice [24, 25] and weight loss in humans resulted in reduced expression in white adipose tissue [25]. Several animal models have demonstrated that absence of inflammasome components is associated with protection from obesity-related insulin resistance [25–27]; though there is inconsistency in this response as another group has shown that obesity-related inflammation was not associated with increased caspase-1 cleavage and Nlrp3 null mice were not protected from adipose tissue inflammation [28]. Lending further credence to a likely role of NRLP3 in obesity and metabolic dysregulation, genome wide association studies (thus far reported in Chinese Han populations) have shown association of an NLRP3 single nucleotide polymorphism with obesity [29] and with type 2 diabetes and insulin resistance [30, 31].…”