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Vasc Med. 2016 Dec;21(6):489-496. Epub 2016 Sep 28.

WNT5A-JNK regulation of vascular insulin resistance in human obesity.

Author information

1
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
2
Department of General Surgery, Boston University School of Medicine, Boston, MA, USA.
3
Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, MA, USA.
4
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA Noyan.Gokce@bmc.org.

Abstract

Obesity is associated with the development of vascular insulin resistance; however, pathophysiological mechanisms are poorly understood. We sought to investigate the role of WNT5A-JNK in the regulation of insulin-mediated vasodilator responses in human adipose tissue arterioles prone to endothelial dysfunction. In 43 severely obese (BMI 44±11 kg/m2) and five metabolically normal non-obese (BMI 26±2 kg/m2) subjects, we isolated arterioles from subcutaneous and visceral fat during planned surgeries. Using videomicroscopy, we examined insulin-mediated, endothelium-dependent vasodilator responses and characterized adipose tissue gene and protein expression using real-time polymerase chain reaction and Western blot analyses. Immunofluorescence was used to quantify endothelial nitric oxide synthase (eNOS) phosphorylation. Insulin-mediated vasodilation was markedly impaired in visceral compared to subcutaneous vessels from obese subjects (p<0.001), but preserved in non-obese individuals. Visceral adiposity was associated with increased JNK activation and elevated expression of WNT5A and its non-canonical receptors, which correlated negatively with insulin signaling. Pharmacological JNK antagonism with SP600125 markedly improved insulin-mediated vasodilation by sixfold (p<0.001), while endothelial cells exposed to recombinant WNT5A developed insulin resistance and impaired eNOS phosphorylation (p<0.05). We observed profound vascular insulin resistance in the visceral adipose tissue arterioles of obese subjects that was associated with up-regulated WNT5A-JNK signaling and impaired endothelial eNOS activation. Pharmacological JNK antagonism markedly improved vascular endothelial function, and may represent a potential therapeutic target in obesity-related vascular disease.

KEYWORDS:

endothelium; insulin resistance; nitric oxide; obesity

PMID:
27688298
PMCID:
PMC5491334
DOI:
10.1177/1358863X16666693
[Indexed for MEDLINE]
Free PMC Article

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