The nuclear retinoid-related orphan receptor RORα controls adipose tissue inflammation in patients with morbid obesity and diabetes

Background/aims Inflammation governs adipose tissue (AT) dysfunction in obesity. Retinoic acid receptor-related orphan receptor alpha (ROR alpha) is associated with inflammation and insulin resistance in animal studies, but its role in human obesity remains elusive. We investigated the expression and function of ROR alpha on AT inflammation in patients with morbid obesity with/without diabetes. Subjects/methods We assessed ROR alpha expression in paired biopsies of subcutaneous and omental AT from 41 patients (body mass index (BMI) 43.3 +/- 0.8 kg/m(2)) during Roux-en-Y-gastric surgery and explored the functional consequences of pharmacological ROR alpha blockade in AT ex vivo. Results ROR alpha expression was significantly higher in omental AT than in subcutaneous AT (p = 0.03) and was positively associated with BMI (r = 0.344, p = 0.027) and homeostasis model assessment of insulin resistance (r = 0.319, p = 0.041). In ex vivo assays, IL-8/CXCL8 and MCP-1/CCL2 chemokine release was significantly higher in omental fat explants from diabetic patients than from non-diabetics and was significantly diminished by ROR alpha blockade (p < 0.05). Inhibition of ROR alpha improved protein kinase B signaling and decreased NF-kappa B activity in omental AT from patients with diabetes (p < 0.05). Under dynamic flow conditions, ROR alpha blockade prevented mononuclear cell attachment to human dysfunctional endothelial cells. Conclusions ROR alpha blockade represents a potential therapy to prevent AT dysfunction and inflammation associated with insulin resistance in human obesity.

Automated summary

ROR alpha expression is higher in omental AT compared to subcutaneous AT, positively correlated with BMI and insulin resistance. Inflammation marker release in omental fat from diabetic patients was reduced significantly by ROR alpha blockade, along with improvement in protein kinase B signaling. The study suggests that ROR alpha blockade could be a potential therapy for preventing AT dysfunction and inflammation in human obesity.