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Molecular Biology

Upregulation of angiostatic chemokines IP-10/CXCL10 and I-TAC/CXCL11 in human obesity and their implication for adipose tissue angiogenesis

International Journal of Obesity volume 42, pages 1406–1417 (2018)Cite this article

Subjects

Abstract

Background/Aims:

Impaired angiogenesis is linked to adipose tissue (AT) dysfunction, inflammation, and insulin resistance in human obesity. Chemokine (C-X-C motif) receptor. (CXCR3) ligands are important regulators of angiogenesis in different disease contexts such as cancer; however, their role in human morbid obesity is unknown. We investigated the role of the CXCR3 axis in AT angiogenesis in morbidly obese patients.

Subjects/Methods:

The study group comprised 50 morbidly obese patients (mean age 44 ± 1 years, body mass index 44 ± 1 kg/m2) who had undergone laparoscopic Roux-Y-gastric bypass surgery, and 25 age-matched non-obese control subjects. We measured the circulating levels of the CXCR3 ligands monokine induced by interferon-γ (MIG/CXCL9), interferon-γ inducible protein 10 (IP-10/CXCL10), and interferon-γ–inducible T-cell alpha chemoattractant (I-TAC/CXCL11) in all studied subjects. Additionally, the expression of CXCR3 ligands was analyzed in paired biopsies of subcutaneous and visceral AT obtained during the laparoscopic procedure in morbidly obese patients. Additionally, we explored the functional role of CXCR3 ligands on angiogenesis in AT from morbidly obese patients using an ex vivo assay.

Results:

Plasma levels of CXCL10 and CXCL11 were significantly higher in morbidly obese patients than in controls (p < 0.01). In ex vivo assays, angiogenic growth was markedly lower in visceral AT than in subcutaneous AT (p < 0.05), which was related to significant tissue upregulation of CXCL10, CXCL11 and CXCR3 (p < 0.05). CXCL10 or CXCL11 inhibited AT angiogenesis (p < 0.05), and blockade of CXCR3 function significantly increased capillary sprouting in visceral fat deposits (p < 0.05). Western blot analysis showed that the p38 mitogen-activated protein kinase signaling pathway was implicated in the angiostatic effects of CXCR3 in AT.

Conclusions:

CXCL10 and CXCL11 may play. deleterious role in obesity as potential inhibitors of AT angiogenesis. Accordingly, pharmacological blockade of CXCR3 could represent. therapy to prevent AT dysfunction in obesity.

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Acknowledgements

We acknowledge financial support by grants CPII13/00025, PI15/00082, PIE15/00013, SAF2014-57845-R, SAF2017-89714-R from the Carlos III Health Institute, the Spanish Ministry of Health, the Spanish Ministry of Economy and Competiveness, and the European Regional Development Fund (FEDER).

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Author notes

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

Authors and Affiliations

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

    Luisa Hueso, Rebeca Ortega, Francisca Selles, Ning Yun Wu-Xiong, Miguel Civera, Juan F Ascaso, Maria-Jesus Sanz, José T Real & Laura Piqueras

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

    Rebeca Ortega, Maria-Jesus Sanz & Laura Piqueras

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

    Ning Yun Wu-Xiong, Miguel Civera, Juan F Ascaso & José T Real

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

    Joaquin Ortega

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

    Joaquin Ortega

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

    Juan F Ascaso & José T Real

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  1. Luisa Hueso
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Correspondence to José T Real or Laura Piqueras.

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Hueso, L., Ortega, R., Selles, F. et al. Upregulation of angiostatic chemokines IP-10/CXCL10 and I-TAC/CXCL11 in human obesity and their implication for adipose tissue angiogenesis. Int J Obes 42, 1406–1417 (2018). https://doi.org/10.1038/s41366-018-0102-5

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