Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA.
Department of Physiology, University of Kentucky, Lexington, KY, USA.
Sci Rep. 2017 Oct 31;7(1):14398. doi: 10.1038/s41598-017-14719-9.
Adipose tissue macrophages have been proposed as a link between obesity and insulin resistance. However, the mechanisms underlying these processes are not completely defined. Calpains are calcium-dependent neutral cysteine proteases that modulate cellular function and have been implicated in various inflammatory diseases. To define whether activated calpains influence diet-induced obesity and adipose tissue macrophage accumulation, mice that were either wild type (WT) or overexpressing calpastatin (CAST Tg), the endogenous inhibitor of calpains were fed with high (60% kcal) fat diet for 16 weeks. CAST overexpression did not influence high fat diet-induced body weight and fat mass gain throughout the study. Calpain inhibition showed a transient improvement in glucose tolerance at 5 weeks of HFD whereas it lost this effect on glucose and insulin tolerance at 16 weeks HFD in obese mice. However, CAST overexpression significantly reduced adipocyte apoptosis, adipose tissue collagen and macrophage accumulation as detected by TUNEL, Picro Sirius and F4/80 immunostaining, respectively. CAST overexpression significantly attenuated obesity-induced inflammatory responses in adipose tissue. Furthermore, calpain inhibition suppressed macrophage migration to adipose tissue in vitro. The present study demonstrates a pivotal role for calpains in mediating HFD-induced adipose tissue remodeling by influencing multiple functions including apoptosis, fibrosis and inflammation.
脂肪组织巨噬细胞被认为是肥胖与胰岛素抵抗之间的联系。然而，这些过程的机制尚未完全确定。钙蛋白酶是一种依赖钙的中性半胱氨酸蛋白酶，可调节细胞功能，并与各种炎症性疾病有关。为了确定激活的钙蛋白酶是否会影响饮食诱导的肥胖和脂肪组织巨噬细胞积聚，用高（60%卡路里）脂肪饮食喂养野生型（WT）或过表达钙蛋白酶抑制剂（CAST Tg）的小鼠 16 周。整个研究过程中，CAST 的过表达并未影响高脂肪饮食诱导的体重和脂肪量增加。钙蛋白酶抑制在 HFD 5 周时短暂改善了葡萄糖耐量，而在 16 周 HFD 时肥胖小鼠的葡萄糖和胰岛素耐量丧失了这种作用。然而，CAST 的过表达显著减少了脂肪细胞凋亡、脂肪组织胶原和巨噬细胞积聚，这分别通过 TUNEL、Picro Sirius 和 F4/80 免疫染色检测到。CAST 的过表达显著减弱了肥胖诱导的脂肪组织炎症反应。此外，钙蛋白酶抑制可抑制巨噬细胞向脂肪组织的迁移。本研究表明钙蛋白酶在介导 HFD 诱导的脂肪组织重塑中起着关键作用，其影响多种功能，包括细胞凋亡、纤维化和炎症。
