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Inflammation and insulin resistance exert dual effects on adipose tissue tumor protein 53 expression

International Journal of Obesity volume 38, pages 737–745 (2014)Cite this article

Subjects

Abstract

Objective:

The purpose of this study was to investigate the expression of human adipose tissue protein 53 (p53) in subjects who varied widely in terms of obesity and insulin resistance. We also analyzed different in vivo and in vitro models to try to comprehend the associations found in humans.

Methods:

p53 was analyzed in human adipose and isolated adipocytes, in high fat-fed and GLP-1R KO mice, during in vitro adipogenesis, and in adipocytes after high glucose, rosiglitazone and inflammatory conditions. The effects of surgery-induced weight loss and ex vivo metformin were also evaluated.

Results:

Omental (OM) p53 gene expression (+27%, P=0.001) and protein (+11%, P=0.04) were increased in obese subjects and high fat diet-induced obese mice (+86%, P=0.018). Although the obesity-associated inflammatory milieu was associated with increased OM p53, this was negatively related to insulin resistance and glycated hemoglobin, and positively with biomarkers for insulin sensitivity. Multiple linear regression analyses revealed that glycated hemoglobin (P<0.0001) and body mass index (P=0.048) contributed independently to explain 13.7% (P<0.0001) of the OM p53 variance. Accordingly, the improvement of insulin sensitivity with surgery-induced weight loss (+51%, P=0.01) and metformin (+42%, P=0.02) led to increased adipose p53. While the glucose-intolerant GLP-1R KO mice showed decreased mesenteric p53 (−45.4%, P=0.017), high glucose led to decreased p53 in pre-adipocytes (−27%, P<0.0001). Inflammatory treatments led to increased p53 (+35%, P<0.0001), while Rs downregulated this expression (−40%, P=0.005) in mature adipocytes.

Conclusion:

Inflammation and insulin resistance exert dual effects on adipose p53, which seems to be the final result of these opposing forces.

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Acknowledgements

We greatly appreciate the technical assistance of Gerard Pardo, Ester Guerra, Oscar Rovira and Roser Rodriguez (Unit of Diabetes, Endocrinology and Nutrition, Institut d’Investigació Biomèdica de Girona; Hospital Universitari de Girona Dr Josep Trueta). The work of all the members of the multidisciplinary obesity team of the Clínica Universitaria de Navarra is also gratefully acknowledged. This work was supported by research grants from the Ministerio de Educación y Ciencia (SAF2011-00214) and the Instituto de Salud Carlos III (ISCIIIRETIC RD06, CIBERObN). RB is a recipient of funding from the Agence Nationale de la Recherche (Florinflam and Floradip programs) as well as from L’Institute Nationale du Diabète.

DISCLAIMER

The contents of this manuscript have not been copyrighted or published previously. There are no directly related manuscripts or abstracts, published or unpublished, by one or more authors of this manuscript. The contents of this manuscript are not now under consideration for publication elsewhere. The submitted manuscript nor any similar manuscript, in whole or in part, will not be copyrighted, submitted or published elsewhere while the Journal is under consideration.

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Authors and Affiliations

  1. CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBERobn, CB06/03/0010), and Instituto de Salud Carlos III (ISCIII), Santiago de Compostela, Spain

    F J Ortega, J M Moreno-Navarrete, D Mayas, W Ricart, F J Tinahones, G Frühbeck & J M Fernández-Real

  2. Service of Diabetes, Endocrinology and Nutrition (UDEN), Institut d’Investigació Biomèdica de Girona (IdIBGi), Hospital “Dr Josep Trueta” of Girona, Girona, Spain

    F J Ortega, J M Moreno-Navarrete, W Ricart & J M Fernández-Real

  3. Service of Endocrinology and Nutrition, Hospital Clínico Universitario Virgen de Victoria de Málaga, Málaga, Spain

    D Mayas & F J Tinahones

  4. INSERM Unité 858, Institut de Médecine Moléculaire de Rangueil, Université Paul Sabatier, IFR31, Toulouse, France

    M Serino, E Luche & R Burcelin

  5. Department of Surgery, Institut d’Investigació Biomèdica de Girona (IdIBGi), Girona, Spain

    J I Rodriguez-Hermosa

  6. Department of Endocrinology & Nutrition, Clínica Universidad de Navarra–CIBERobn CBO6/03/1014, Pamplona, Spain

    G Frühbeck

  7. Institute of Internal Medicine, Catholic University of Rome, Rome, Italy

    G Mingrone

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  1. F J Ortega
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Corresponding authors

Correspondence to F J Ortega or J M Fernández-Real.

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Additional information

All authors of this manuscript have directly participated in the execution and analysis of the study and have approved the final version submitted. FJO designed the study, analyzed the biochemical variables, performed the statistical analysis and wrote the manuscript. JMM-N, DM and MS analyzed the biochemical variables. JIR-H obtained the biopsies, the anthropometrical characteristics and the written consent of volunteers. EL and RB were responsible for mice, and the mouse models of obesity and high-fat diet. GM obtained subcutaneous fat samples from morbid obese volunteers before and after bariatric surgery. WR, RB, FT, GF and GM provided important intellectual content. AZ also carried out the conception of the study. JMF-R carried out the conception and coordination of the study, and contributed to writing the manuscript.

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Ortega, F., Moreno-Navarrete, J., Mayas, D. et al. Inflammation and insulin resistance exert dual effects on adipose tissue tumor protein 53 expression. Int J Obes 38, 737–745 (2014). https://doi.org/10.1038/ijo.2013.163

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