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

Autores de INCLIVA

• Rebeca Ortega Herraiz

  Autor

• Luisa Maria Hueso Soler

  Autor

• Esther Benito Casado

  Autor

• Joaquin Ortega Serrano

  Autor

• Miguel Civera Andres

  Autor

• 

  Maria Jesus Sanz Ferrando

  Autor

• 

  Jose Tomas Real Collado

  Autor

• 

  Laura Piqueras Ruiz

  Autor

Grupos y Plataformas de I+D+i

• Grupo de Investigación en Cirugía General y Digestiva

  

  Leading Researcher

  Luis Sabater Orti

• Grupo de Investigación en Inflamación

  

  Leading Researcher

  Maria Jesus Sanz Ferrando

• Grupo de Investigación en Receptores Nucleares en Patología Cardiometabólicas

  

  Established Researcher

  Laura Piqueras Ruiz

• Grupo de Investigación sobre Riesgo Cardiometabólico y Diabetes

  

  Leading Researcher

  Sergio Martinez Hervas

Abstract

BACKGROUND/AIMS: Inflammation governs adipose tissue (AT) dysfunction in obesity. Retinoic acid receptor-related orphan receptor alpha (RORa) 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 RORa on AT inflammation in patients with morbid obesity with/without diabetes. SUBJECTS/METHODS: We assessed RORa 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 RORa blockade in AT ex vivo. RESULTS: RORa 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 RORa blockade (p < 0.05). Inhibition of RORa improved protein kinase B signaling and decreased NF-?B activity in omental AT from patients with diabetes (p < 0.05). Under dynamic flow conditions, RORa blockade prevented mononuclear cell attachment to human dysfunctional endothelial cells. CONCLUSIONS: RORa blockade represents a potential therapy to prevent AT dysfunction and inflammation associated with insulin resistance in human obesity.