Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity

The comprehensive assessment of long term effects of reducing intake of energy, CALERIE II, clinical trial established that caloric restriction, CR, in humans lowers inflammation. The identity and mechanism of endogenous CR mimetics that can be deployed to control obesity associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14 percent sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine, SPARC, in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low protein diet feeding decreased, while high fat diet induced, obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked effects of CR on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against high fat diet induced adiposity, chronic inflammation, and metabolic dysfunction. Mechanistically, SPARC activates the NLRP3 inflammasome at the priming step and downregulation of SPARC lowers macrophage inflammation in adipose tissue, while excess SPARC activated macrophages via JNK signaling. Collectively, reduction of adipocyte derived SPARC confers CR like metabolic and antiinflammatory benefits in obesity by serving as an immunometabolic checkpoint of inflammation.