IRhom2 Ablation Mitigates Obesity by Suppressing Pro-Inflammatory Macrophage Activation-Triggered Adipose Inflammation

Abstract

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. 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 or a high-fat diet (HFD; 60% fat calories). Then the adipose tissues or bone-marrow cells were isolated for the further detection. 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. Also, we further demonstrated that, in response to an HFD, iRhom2 KO mice and mice with deletion only in myeloid cells showed less severe adipose inflammation and insulin resistance than that of control groups. Conversely, transplantation of bone-marrow cells from normal mice to iRhom2 KO mice unleashed a severity of systemic inflammation and metabolic dysfunction after HFD ingestion. We identify iRhom2 as a key regulator that promotes obesity-associated metabolic disorders. Loss of iRhom2 from macrophages in adipose tissues inhibited inflammation and insulin resistance. Hence, iRhom2 may be a therapeutic target for obesity-induced metabolic dysfunction. Funding Statement: This work was jointly supported by (1) National Natural Science Foundation of China (NSFC Grant No.: 81703527); (2) Chongqing Research Program of Basic Research and Frontier Technology (Grant No.: cstc2017jcyjAX0356, cstc2018jcyjA3686, cstc2018jcyjAX0784, cstc2018jcyjA1472, cstc2018jcyjAX0811, cstc2018jcyjA3533 and KJZD-M201801601); (3) School-level Research Program of Chongqing University of Education (Grant No.: KY201710B and 17GZKP01); (4) Advanced Programs of Post-doctor of Chongqing (Grant No.: 2017LY39); (5) Science and Technology Research Program of Chongqing Education Commission of China (Grant No.: KJQN201901608, KJQN201901615, KJ1601402) and (6) Children's Research Institute of National Center for Schooling Development Programme and Chongqing University of Education (Grant No.: CSDP19FSO1108). Declaration of Interests: Minxuan Xu, Chenxu Ge, Yuting Qin, Deshuai Lou, Qiang Li, Jing Feng, Yekuan Wu , Linfeng Hu, Bochu Wang & Jun Tan declare that they have no conflict of interest. Ethics Approval Statement: All research procedures associating with mice were approved by the Institutional Animal Care and Use Committee in Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological and Chemical Engineering, Chongqing University of Education, and were performed in accordance with the Guide for the Care and Use of Laboratory Animals, issued by the National Institutes of Health in 1996. The protocols used in this study were in accordance with the Regulations of Experimental Animal Administration issued by the Ministry of Science and Technology of the People's Republic of China.