Inflammation Program, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA, USA; Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA, USA; Immunology Graduate Program, Iowa City, IA, USA.
Department of Internal Medicine, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA, USA; Division of Endocrinology and Metabolism, Fraternal Order of Eagles Diabetes Research Center, Roy J. and Lucille A. Carver College of Medicine University of Iowa, Iowa City, IA, USA.
Metabolism. 2020 May;106:154194. doi: 10.1016/j.metabol.2020.154194. Epub 2020 Mar 2.
Low-grade inflammation and metabolic dysregulation are common comorbidities of obesity, both of which are associated with alterations in iRhom2-regulated pro-inflammatory cytokine and epidermal growth factor receptor (EGFR) ligand signaling.
Our objective was to determine the role of iRhom2 in the regulation of low-grade inflammation and metabolic dysregulation in a murine model of diet-induced obesity.
Wild type (WT) and iRhom2-deficient mice were fed normal chow (NC) or a high-fat diet (HFD) starting at 5 weeks of age for up to 33 weeks. Body composition, glucose and insulin tolerance, feeding behavior, and indirect calorimetry were measured at defined time points. Adipose tissue cytokine expression and inflammatory lesions known as crown-like structures (CLS) were analyzed at the end-point of the study.
iRhom2-deficient mice show accelerated fat gain on a HFD, accompanied by insulin resistance. Indirect calorimetry did not demonstrate changes in energy expenditure or food intake, but locomotor activity was significantly reduced in HFD iRhom2-deficient mice. Interestingly, CLS, macrophage infiltration, and tumor necrosis factor (TNF) production were decreased in adipose tissue from HFD iRhom2-deficient mice, but circulating cytokines were unchanged. In inguinal and perigonadal fat, the EGFR ligand amphiregulin was markedly induced in HFD controls but completely prevented in iRhom2-deficient mice, suggesting a potentially dominant role of EGFR-dependent mechanisms over TNF in the modulation of insulin sensitivity.
This study elucidates a novel role for iRhom2 as an immuno-metabolic regulator that affects adipose tissue inflammation independent of insulin resistance.
低度炎症和代谢失调是肥胖的常见合并症，两者都与 iRhom2 调节的促炎细胞因子和表皮生长因子受体 (EGFR) 配体信号的改变有关。
我们的目的是确定 iRhom2 在饮食诱导肥胖的小鼠模型中调节低度炎症和代谢失调中的作用。
从 5 周龄开始，野生型 (WT) 和 iRhom2 缺陷型小鼠分别喂食正常饲料 (NC) 或高脂肪饮食 (HFD)，持续 33 周。在规定的时间点测量身体成分、葡萄糖和胰岛素耐量、摄食行为和间接测热法。在研究结束时分析脂肪组织细胞因子表达和称为冠状结构 (CLS) 的炎症病变。
iRhom2 缺陷型小鼠在 HFD 上表现出加速脂肪堆积，伴有胰岛素抵抗。间接测热法并未显示能量消耗或食物摄入的变化，但 HFD iRhom2 缺陷型小鼠的运动活动明显减少。有趣的是，HFD iRhom2 缺陷型小鼠脂肪组织中的 CLS、巨噬细胞浸润和肿瘤坏死因子 (TNF) 产生减少，但循环细胞因子不变。在腹股沟和腹膜后脂肪中，HFD 对照中 EGFR 配体 Amphiregulin 明显诱导，但在 iRhom2 缺陷型小鼠中完全被阻止，这表明 EGFR 依赖性机制在调节胰岛素敏感性方面可能比 TNF 更为重要。
这项研究阐明了 iRhom2 作为一种免疫代谢调节剂的新作用，它独立于胰岛素抵抗影响脂肪组织炎症。
