WNT5A-JNK regulation of vascular insulin resistance in human obesity

Vasc Med. 2016 Dec;21(6):489-496. doi: 10.1177/1358863X16666693. Epub 2016 Sep 28.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adiposity*
  • Adolescent
  • Adult
  • Arterioles / drug effects*
  • Arterioles / enzymology
  • Arterioles / physiopathology
  • Case-Control Studies
  • Cells, Cultured
  • Endothelium, Vascular / drug effects*
  • Endothelium, Vascular / enzymology
  • Endothelium, Vascular / physiopathology
  • Female
  • Humans
  • In Vitro Techniques
  • Insulin / pharmacology*
  • Insulin Resistance*
  • Intra-Abdominal Fat / blood supply*
  • JNK Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • Male
  • Middle Aged
  • Nitric Oxide Synthase Type III / metabolism
  • Obesity / enzymology*
  • Obesity / physiopathology
  • Phosphorylation
  • Protein Kinase Inhibitors / pharmacology
  • Vasodilation / drug effects*
  • Vasodilator Agents / pharmacology*
  • Wnt Signaling Pathway / drug effects*
  • Wnt-5a Protein / metabolism*
  • Young Adult


  • Insulin
  • Protein Kinase Inhibitors
  • Vasodilator Agents
  • WNT5A protein, human
  • Wnt-5a Protein
  • NOS3 protein, human
  • Nitric Oxide Synthase Type III
  • JNK Mitogen-Activated Protein Kinases