Functional loss of inactive rhomboid-like protein 2 mitigates obesity by suppressing pro-inflammatory macrophage activation-triggered adipose inflammation.,Molecular Metabolism

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Functional loss of inactive rhomboid-like protein 2 mitigates obesity by suppressing pro-inflammatory macrophage activation-triggered adipose inflammation.
Molecular Metabolism ( IF 7.0 ) Pub Date : 2020-01-22 , DOI: 10.1016/j.molmet.2020.01.008
Minxuan Xu ₁ , Chenxu Ge ₁ , Yuting Qin ₂ , Deshuai Lou ₃ , Qiang Li ₃ , Jing Feng ₃ , Yekuan Wu ₃ , Linfeng Hu ₃ , Bochu Wang ₄ , Jun Tan ₃

Affiliation

Objective

Chronic inflammation of adipose tissues contributes to obesity-triggered insulin resistance. Unfortunately, the potential molecular mechanisms regarding obesity-associated systemic inflammation and metabolic disorder remain complicated. Here, we report that inactive rhomboid-like protein 2 (iRhom2) was increased in overweight mice with adipose inflammation.

Methods

Mice with deletion of iRhom2 on a C57BL/6J background, mice without deletion of this gene (controls), and mice with deficiency of iRhom2 only in myeloid cells were fed a standard chow diet (SCD) or a high-fat diet (HFD; 60% fat calories). Then the adipose tissues or bone marrow cells were isolated for the further detection.

Results

After 16 weeks on a high-fat diet (HFD), obesity, chronic inflammation in adipose tissues, and insulin resistance were markedly mitigated in iRhom2 knockout (iRhom2 KO) mice, whereas these parameters were exaggerated in iRhom2 overactivated mice. The adverse influences of iRhom2 on adipose inflammation and associated pathologies were determined in db/db mice. We further demonstrated that, in response to an HFD, iRhom2 KO mice and mice with deletion only in the myeloid cells showed less severe adipose inflammation and insulin resistance than control groups. Conversely, transplantation of bone marrow cells from normal mice to iRhom2 KO mice unleashed severe systemic inflammation and metabolic dysfunction after HFD ingestion.

Conclusion

We identified iRhom2 as a key regulator that promotes obesity-associated metabolic disorders. Loss of iRhom2 from macrophages in adipose tissues may indirectly restrain inflammation and insulin resistance via blocking crosslinks between macrophages and adipocytes. Hence, iRhom2 may be a therapeutic target for obesity-induced metabolic dysfunction.

中文翻译：

失活的菱形样蛋白2的功能丧失可通过抑制促炎性巨噬细胞活化触发的脂肪炎症来减轻肥胖。

目的

脂肪组织的慢性炎症有助于肥胖引发的胰岛素抵抗。不幸的是，关于肥胖相关的全身性炎症和代谢紊乱的潜在分子机制仍然很复杂。在这里，我们报告失活的菱形样蛋白2（iRhom2）在肥胖发胖的超重小鼠中增加。

方法

在C57BL / 6J背景下缺失iRhom2的小鼠，未缺失该基因的小鼠（对照组）和仅在髓样细胞中缺乏iRhom2的小鼠接受标准的日粮（SCD）或高脂饮食（HFD; 60％的脂肪卡路里）。然后分离出脂肪组织或骨髓细胞用于进一步检测。

结果

使用高脂饮食（HFD）16周后，iRhom2基因敲除（iRhom2 KO）小鼠的肥胖，脂肪组织的慢性炎症和胰岛素抵抗显着缓解，而iRhom2过度激活的小鼠则夸大了这些参数。在db / db小鼠中确定了iRhom2对脂肪炎症和相关病理的不利影响。我们进一步证明，对HFD的反应，iRhom2 KO小鼠和仅在髓样细胞中缺失的小鼠表现出比对照组更不严重的脂肪炎症和胰岛素抵抗。相反，从HFD摄入后，正常小鼠骨髓细胞向iRhom2 KO小鼠的移植释放出严重的全身炎症和代谢功能障碍。