Abstract
Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Here we report that the interleukin-36 (IL-36) subfamily can play a protective role against the development of disease. Elevated IL-36 cytokine expression is found in the serum of obese patients and negatively correlates with blood glucose levels among those presenting with type 2 diabetes. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance. These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. IL-36 cytokines promote its outgrowth as well as increased colonic mucus secretion. These findings identify a protective role for IL-36 cytokines in obesity and metabolic disease, adding to the current understanding of the role the broader IL-1 family plays in regulating disease pathogenesis.
Highlights
Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles
We demonstrate that IL-36γ expression is increased in the serum of clinically obese patients and these elevated expression levels are negatively correlated with both haemoglobin A1c (HbA1c) and fasting blood glucose (FBG) levels among patients with type 2 diabetes indicating a protective role for these cytokines in countering metabolic dysfunction
In an effort to determine whether the IL-36 family of cytokines may play a role in the development of obesity and metabolic disease, we investigated serum expression levels of the IL-36 family among a cohort of adult patients presenting with clinical obesity (BMI>30 kg/ m2), with or without signs of diabetes, as determined by serum HbA1c levels, according to American Diabetes Association guidelines[25]
Summary
Members of the interleukin-1 (IL-1) family are important mediators of obesity and metabolic disease and have been described to often play opposing roles. Mice lacking IL-36Ra, an IL-36 family signalling antagonist, develop less diet-induced weight gain, hyperglycemia and insulin resistance These protective effects correlate with increased abundance of the metabolically protective bacteria Akkermansia muciniphila in the intestinal microbiome. It is evident that changes in the homoeostatic barrier function of the gut can play a major role in the development of systemic inflammation in obesity[5] In this context, it is perhaps unsurprising that the constituents of the intestinal microbiome are emerging as an important factor in this regard. The role of the microbiota in the development of obesity-driven metabolic disease first emerged from studies on germ-free mice, which demonstrated reduced levels of experimental weight gain and improved glucose tolerance[6,7]. Such observations suggest that the composition of the intestinal microbiome can be altered towards a more ‘healthy’ lean state, highlighting its potential as a therapeutic strategy, and placing the identification of the mechanistic pathways which can alter the composition of the microbiota as a particular area of interest
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