Plasma from pre-pubertal obese children impairs insulin stimulated Nitric Oxide (NO) bioavailability in endothelial cells: Role of ER stress.

Change log
Di Pietro, Natalia 
Marcovecchio, M Loredana 
Di Silvestre, Sara 
de Giorgis, Tommaso 
Cordone, Vincenzo Giuseppe Pio 

Childhood obesity is commonly associated with early signs of endothelial dysfunction, characterized by impairment of insulin signaling and vascular Nitric Oxide (NO) availability. However, the underlying mechanisms remain to be established. Hence, we tested the hypothesis that endothelial insulin-stimulated NO production and availability was impaired and related to Endoplasmic Reticulum (ER) in human umbilical vein endothelial cells (HUVECs) cultured with plasma obtained from pre-pubertal obese (OB) children. OB children (N = 28, age: 8.8 ± 2.2; BMI z-score: 2.15 ± 0.39) showed impaired fasting glucose, insulin and HOMA-IR than normal weight children (CTRL; N = 28, age: 8.8 ± 1.7; BMI z-score: 0.17 ± 0.96). The in vitro experiments showed that OB-plasma significantly impaired endothelial insulin-stimulated NO production and bioavailability compared to CTRL-plasma. In parallel, in HUVECs OB-plasma increased GRP78 and activated PERK, eIF2α, IkBα and ATF6 (all ER stress markers). Moreover, OB-plasma increased NF-κB activation and its nuclear translocation. Notably, all these effects proved to be significantly restored by using PBA and TUDCA, known ER stress inhibitors. Our study demonstrate for the first time that plasma from obese children is able to induce in vitro endothelial insulin resistance, which is characterized by reduced insulin-stimulated NO production and bioavailability, endothelial ER stress and increased NF-κB activation.

ER stress, Endothelial dysfunction, Insulin resistance, Nitric oxide, Obesity, Activating Transcription Factor 6, Biological Availability, Biomarkers, Cell Nucleus, Child, Cyclic GMP, Endoplasmic Reticulum Chaperone BiP, Endoplasmic Reticulum Stress, Human Umbilical Vein Endothelial Cells, Humans, Insulin, Models, Biological, NF-kappa B, Nitric Oxide, Nitric Oxide Synthase Type III, Obesity, Phosphorylation, Protein Transport, Proto-Oncogene Proteins c-akt, Puberty
Journal Title
Mol Cell Endocrinol
Conference Name
Journal ISSN
Volume Title
Elsevier BV