WNT5A-JNK regulation of vascular insulin resistance in human obesity.
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.
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Melissa G
MG
Farb
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Shakun
S
Karki
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Song-Young
SY
Park
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Samantha M
SM
Saggese
Department of General Surgery, Boston University School of Medicine, Boston, MA, USA.
Brian
B
Carmine
Department of General Surgery, Boston University School of Medicine, Boston, MA, USA.
Donald T
DT
Hess
Department of Medicine, Section of Endocrinology, Diabetes and Nutrition, Boston University School of Medicine, Boston, MA, USA.
Caroline
C
Apovian
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Jessica L
JL
Fetterman
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Rosa
R
Bretón-Romero
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Naomi M
NM
Hamburg
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
José J
JJ
Fuster
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
María A
MA
Zuriaga
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA.
Kenneth
K
Walsh
Department of Medicine and Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston, MA, USA Noyan.Gokce@bmc.org.
Noyan
N
Gokce
D050154:Adiposity; D000293:Adolescent; D000328:Adult; D001160:Arterioles / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology*; D007333:Insulin Resistance; D050152:Intra-Abdominal Fat / Q000098:blood supply*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009765:Obesity / Q000201:enzymology* / Q000503:physiopathology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D000071818:Wnt-5a Protein / Q000378:metabolism*; D055815:Young Adult
D007328:Insulin; D047428:Protein Kinase Inhibitors; D014665:Vasodilator Agents; C085389:WNT5A protein, human; D000071818:Wnt-5a Protein; C496314:NOS3 protein, human; D052250:Nitric Oxide Synthase Type III; D048031:JNK Mitogen-Activated Protein Kinases
endothelium; insulin resistance; nitric oxide; obesity
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