Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity
Seungjin Ryu, … , Yun-Hee Youm, Vishwa Deep Dixit
Seungjin Ryu, … , Yun-Hee Youm, Vishwa Deep Dixit
Published October 2, 2023
Citation Information: J Clin Invest. 2023;133(19):e169173. https://doi.org/10.1172/JCI169173.
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Research Article Inflammation Metabolism

Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity

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.

Authors

Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit

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Figure 8

SPARC activates inflammation in macrophages via JNK signaling.

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SPARC activates inflammation in macrophages via JNK signaling. (A) Human...
(A) Human SPARC or mock vector was overexpressed in RAW 264.7 cells by transient transfection (0.5 and 2.5 μg) and Western-blot analyses of SPARC, JNK and p38 MAPK are shown. The experiment was repeated in triplicate and performed twice. (B) q-PCR analysis of Il1b, Tnf, Nos2, and Il6 in RAW 264.7 cells with SPARC or mock vector overexpression. (C) Primary BMDMs were treated with SPARC (5–60 minutes) and JNK, p65 NF-κB, and p38 MPAK were quantified by immunoblot analysis. (D) Representative immunoblot of p-p65 NF-κB in BMDMs pretreated with STAT1, p38, and JNK inhibitor and in presence of SPARC (20 μg/mL). (E) q-PCR analysis of Il1b, Tnf, Nos2, and Il6 in BMDMs pretreated with p38 or JNK inhibitor followed by SPARC treatment (20 μg/mL). (F) Primary BMDMs were transfected with JNK and STAT1 siRNA and immunoblot analysis was performed to quantify Pro-IL-1β protein levels. The experiment was repeated in triplicate and performed twice. Error bars represent the mean ± SEM. 2-tailed unpaired t tests (B) and 1-way ANOVA test with Bonferroni’s multiple comparisons test for adjusted P values (E) were performed for statistical analysis. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.