iRhom2 serves as a facilitator in obesity by enhancing adipose inflammation and insulin resistance

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 display that inactive rhomboid-like protein 2 (iRhom2) is increased in mice fat with adipose inflammation. After 16 weeks on a high fat diet (HFD), obesity, chronic inflammation in adipose tissues and insulin resistance are markedly mitigated in iRhom2-knockout (iRhom2 KO) mice, but exaggerated in iRhom2-overactivated mice. The adverse impressions of iRhom2 on adipose inflammation and associated pathologies are determined in db/db mice. Also, we further exhibit that in response to HFD, iRhom2 KO mice and mice with deletion only in myeloid cells showed less severe adipose inflammation and insulin resistance than the control groups. Conversely, transplantation of bone marrow cells from normal mice to iRhom2 KO mice unleashed the severity of systemic inflammation and metabolic dysfunction after HFD ingestion. In conclusion, we identify iRhom2 as a key regulator that promotes obesity-associated metabolic disorder. Loss of iRhom2 from macrophages in adipose tissues inhibited the inflammation and insulin resistance. iRhom2 might be a therapeutic target for obesity-induced metabolic dysfunction.