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Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity
Seungjin Ryu1,2,3, Olga Spadaro1,2, Sviatoslav Sidorov1,2
1Department of Pathology and.
Abstract:
The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) 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% 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 (HFD-induced) obesity increased SPARC expression in adipose tissue. Inducible SPARC downregulation in adult mice mimicked CR's effects on lowering adiposity by regulating energy expenditure. Deletion of SPARC in adipocytes was sufficient to protect mice against HFD-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.
Insights
Caloric restriction (CR) reduces inflammation. This study identifies secreted protein acidic and rich in cysteine (SPARC) as a key mediator, showing its reduction mimics CR benefits for obesity and inflammation.
Area of Science:
- Immunology
- Metabolic Disease
- Obesity Research
Background:
- Caloric restriction (CR) is known to reduce inflammation in humans.
- The endogenous mechanisms and molecules (CR-mimetics) that mediate CR's anti-inflammatory effects in obesity are not fully understood.
- Secreted protein acidic and rich in cysteine (SPARC) is a matricellular protein implicated in tissue remodeling.
Purpose of the Study:
- To investigate the role of SPARC in obesity-associated inflammation and its potential as a CR-mimetic.
- To elucidate the mechanism by which SPARC influences inflammation in adipose tissue.
Main Methods:
- Analysis of SPARC expression in adipose tissue from humans undergoing CR (CALERIE-II trial).
- Studies in mice involving diet-induced obesity (DIO), CR, low-protein diets, inducible SPARC downregulation, and adipocyte-specific SPARC deletion.
- Investigation of SPARC's effect on NLRP3 inflammasome activation and macrophage inflammation via JNK signaling.
Main Results:
- Sustained CR in humans for 2 years reduced SPARC expression in adipose tissue.
- In mice, CR and low-protein diets decreased SPARC in adipose tissue, while HFD-induced obesity increased it.
- SPARC downregulation in mice mimicked CR's effects on adiposity and energy expenditure.
- SPARC deletion in adipocytes protected mice from HFD-induced obesity, inflammation, and metabolic dysfunction.
- SPARC activates the NLRP3 inflammasome and promotes macrophage inflammation via JNK signaling.
Conclusions:
- Adipocyte-derived SPARC plays a critical role in obesity-associated inflammation and metabolic dysfunction.
- Reducing SPARC confers CR-like metabolic and anti-inflammatory benefits, suggesting it acts as an immunometabolic checkpoint.
- Targeting SPARC may offer a therapeutic strategy for managing obesity and related inflammatory diseases.
