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Clinical Research

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

International Journal of Obesity volume 45, pages 1369–1381 (2021)Cite this article

Subjects

Abstract

Background/aims

Inflammation governs adipose tissue (AT) dysfunction in obesity. Retinoic acid receptor-related orphan receptor alpha (RORα) 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 RORα on AT inflammation in patients with morbid obesity with/without diabetes.

Subjects/methods

We assessed RORα expression in paired biopsies of subcutaneous and omental AT from 41 patients (body mass index (BMI) 43.3 ± 0.8 kg/m2) during Roux-en-Y-gastric surgery and explored the functional consequences of pharmacological RORα blockade in AT ex vivo.

Results

RORα 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 RORα blockade (p < 0.05). Inhibition of RORα improved protein kinase B signaling and decreased NF-κB activity in omental AT from patients with diabetes (p < 0.05). Under dynamic flow conditions, RORα blockade prevented mononuclear cell attachment to human dysfunctional endothelial cells.

Conclusions

RORα blockade represents a potential therapy to prevent AT dysfunction and inflammation associated with insulin resistance in human obesity.

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Fig. 1: RORα expression in paired subcutaneous and omental adipose tissue from morbid obese subjects.
Fig. 2: RORα expression in morbidly obese subjects with or without diabetes.
Fig. 3: Chemokine release in adipose tissue explants from diabetic and non-diabetic morbid obese subjects.
Fig. 4: Effects of RORα inhibition on AKT and p65 NF-κB signaling in omental fat from diabetic and non-diabetic morbid obese patients.
Fig. 5: Effects of RORα inhibition on mononuclear cell-endothelium recruitment under physiological flow conditions.

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Acknowledgements

This work was supported by grants from the Carlos III Health Institute/ Spanish Ministry of Health (PI18/00209, PI15/00082) and the Spanish Ministry of Economy and Competitiveness (SAF2017-89714-R), Generalitat Valenciana (grants Gent T CDEI-04/20-A and AICO/2019/250) and the European Regional Development Fund (FEDER). Hueso L holds a predoctoral grant from Carlos III Health Institute (FI19/00033). Piqueras L is under a “Plan GenT” contract (CDEI-04/20-A) (Conselleria de Sanidad, Valencia, Spain). The authors gratefully acknowledge the valuable collaboration of all the members of the multidisciplinary research Team of CIBERDEM: Diabetes and Associated Metabolic Diseases Networking Biomedical Research.

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Author notes

  1. These authors contributed equally: Rebeca Ortega, Luisa Hueso

Authors and Affiliations

  1. Institute of Health Research-INCLIVA, Valencia, Spain

    Rebeca Ortega, Luisa Hueso, Esther Benito, Miguel Civera, Maria-Jesus Sanz, José T. Real & Laura Piqueras

  2. Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain

    Rebeca Ortega, Luisa Hueso, Maria-Jesus Sanz & Laura Piqueras

  3. Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Valencia, Spain

    Esther Benito, Miguel Civera & José T. Real

  4. CIBERDEM: Diabetes and Associated Metabolic Diseases Networking Biomedical Research- ISCIII, Madrid, Spain

    Esther Benito, Maria-Jesus Sanz, José T. Real & Laura Piqueras

  5. Surgery Service, University Clinic Hospital of Valencia, Valencia, Spain

    Joaquín Ortega

  6. Department of Surgery, University of Valencia, Valencia, Spain

    Joaquín Ortega

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  1. Rebeca Ortega
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Contributions

Data curation, RO, and LH; formal analysis, RO, LH, MC, MJS, LP, and JTR; funding acquisition, LP, MJS, and JTR; investigation, RO, LH; methodology, RO, LH, EB, MC, JO, MJS, JTR, and LP; supervision, LP, MJS, and JTR; conceptualization and writing-original draft, LP; writing-review & editing, RO, LH, EB, MC, JO, MJS, JTR, and LP. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Maria-Jesus Sanz, José T. Real or Laura Piqueras.

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Ortega, R., Hueso, L., Benito, E. et al. The nuclear retinoid‐related orphan receptor RORα controls adipose tissue inflammation in patients with morbid obesity and diabetes. Int J Obes 45, 1369–1381 (2021). https://doi.org/10.1038/s41366-021-00787-5

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