Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity.
Reduction of SPARC protects mice against NLRP3 inflammasome activation and obesity.
复制标题
DOI：
10.1172/jci169173
复制
发表时间：
2023-10-02
影响因子：
15.9
通讯作者：
Dixit, Vishwa Deep
中科院分区：
文献类型：
--
作者：
Ryu, Seungjin;Spadaro, Olga;Sidorov, Sviatoslav;Lee, Aileen H.;Caprio, Sonia;Morrison, Christopher;Smith, Steven R.;Ravussin, Eric;Shchukina, Irina;Artyomov, Maxim N.;Youm, Yun-Hee;Dixit, Vishwa Deep
对减少能量摄入的长期影响的综合评估（CALERIE-II；NCT00427193）临床试验证实，人体热量限制（CR）可以降低炎症。可用于控制肥胖相关炎症和疾病的内源性 CR 模拟物的特性和机制尚不清楚。我们的研究发现，人体持续 2 年的 14% CR 会抑制脂肪组织中基质细胞蛋白、富含半胱氨酸的酸性分泌蛋白 (SPARC) 的表达。在小鼠中，通过 CR 和低蛋白饮食喂养减轻体重引起的脂肪组织重塑减少，而高脂肪饮食诱导（HFD 诱导）的肥胖则增加了脂肪组织中 SPARC 的表达。成年小鼠中诱导性 SPARC 下调模仿了 CR 通过调节能量消耗来降低肥胖的效果。脂肪细胞中 SPARC 的缺失足以保护小鼠免受 HFD 诱导的肥胖、慢性炎症和代谢功能障碍的影响。从机制上讲，SPARC 在启动步骤激活 NLRP3 炎症小体，SPARC 的下调可降低脂肪组织中的巨噬细胞炎症，而过量的 SPARC 通过 JNK 信号传导激活巨噬细胞。总的来说，脂肪细胞来源的 SPARC 的减少通过充当炎症的免疫代谢检查点，为肥胖症提供了类似 CR 的代谢和抗炎益处。
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.