Luisa Hueso1, Rebeca Ortega1,2, Francisca Selles1, Ning Yun Wu-Xiong1,3, Joaquin Ortega4,5, Miguel Civera1,3, Juan F Ascaso1,3,6, Maria-Jesus Sanz1,2, José T Real7,8,9, Laura Piqueras10,11. 1. Institute of Health Research-INCLIVA, Valencia, Spain. 2. Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain. 3. Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Valencia, Spain. 4. Surgery Service, University Clinic Hospital of Valencia, Valencia, Spain. 5. Department of Surgery, University of Valencia, Valencia, Spain. 6. CIBERDEM: Diabetes and Associated Metabolic Diseases Networking Biomedical Research- ISCIII, Madrid, Spain. 7. Institute of Health Research-INCLIVA, Valencia, Spain. Jose.T.Real@uv.es. 8. Endocrinology and Nutrition Service, University Clinic Hospital of Valencia, Valencia, Spain. Jose.T.Real@uv.es. 9. CIBERDEM: Diabetes and Associated Metabolic Diseases Networking Biomedical Research- ISCIII, Madrid, Spain. Jose.T.Real@uv.es. 10. Institute of Health Research-INCLIVA, Valencia, Spain. piqueras_lau@gva.es. 11. Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain. piqueras_lau@gva.es.
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.
BACKGROUND/AIMS: Impaired angiogenesis is linked to adipose tissue (AT) dysfunction, inflammation, and insulin resistance in humanobesity. 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 obesepatients. SUBJECTS/ METHODS: The study group comprised 50 morbidly obesepatients (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 obesepatients. Additionally, we explored the functional role of CXCR3 ligands on angiogenesis in AT from morbidly obesepatients using an ex vivo assay. RESULTS: Plasma levels of CXCL10 and CXCL11 were significantly higher in morbidly obesepatients 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.
Authors: Live Marie T Stokkeland; Guro F Giskeødegård; Mariell Ryssdal; Anders Hagen Jarmund; Bjørg Steinkjer; Torfinn Støve Madssen; Signe N Stafne; Solhild Stridsklev; Tone S Løvvik; Ann-Charlotte Iversen; Eszter Vanky Journal: J Clin Endocrinol Metab Date: 2022-01-01 Impact factor: 5.958