Retinoic acid receptor-related orphan receptor stimulates adipose tissue inflammation by modulating endoplasmic reticulum stress

Adipose tissue inflammation has been linked to metabolic diseases such as obesity and type 2 diabetes. However, the molecules that mediate inflammation in adipose tissue have not been addressed. Although retinoic acid receptor-related orphan receptor (ROR) is known to be involved in the regulation of inflammatory response in some tissues, its role is largely unknown in adipose tissue. Conversely, it is known that endoplasmic reticulum (ER) stress and unfolding protein response (UPR) signaling affect the inflammatory response in obese adipose tissue, but whether ROR regulates these processes remains unknown. In this study, we investigate the link between ROR and adipose tissue inflammation. We showed that the inflammatory response in macrophages or 3T3-L1 adipocytes stimulated by lipopolysaccharide, as well as adipose tissue in obese mice, markedly increased the expression of ROR. Adenovirus-mediated overexpression of ROR or treatment with the ROR-specific agonist SR1078 enhanced the expression of inflammatory cytokines and increased the number of infiltrated macrophages into adipose tissue. Furthermore, SR1078 up-regulated the mRNA expression of ER stress response genes and enhanced phosphorylations of two of the three mediators of major UPR signaling pathways, PERK and IRE1. Finally, we found that alleviation of ER stress using a chemical chaperone followed by the suppression of ROR induced inflammation in adipose tissue. Our data suggest that ROR-induced ER stress response potentially contributes to the adipose tissue inflammation that can be mitigated by treatment with chemical chaperones. The relationships established here between ROR expression, inflammation, and UPR signaling may have implications for therapeutic targeting of obesity-related metabolic diseases.