WNT5A-JNK regulation of vascular insulin resistance in human obesity

Melissa G. Farb, Shakun Karki, Song Young Park, Samantha M. Saggese, Brian Carmine, Donald T. Hess, Caroline Apovian, Jessica L. Fetterman, Rosa Bretón-Romero, Naomi M. Hamburg, José J. Fuster, María A. Zuriaga, Kenneth Walsh, Noyan Gokce

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)489-496
Number of pages8
JournalVascular Medicine
Volume21
Issue number6
DOIs
StatePublished - Dec 1 2016
Externally publishedYes

Keywords

  • endothelium
  • insulin resistance
  • nitric oxide
  • obesity

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine

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