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Forkhead box O-1 modulation improves endothelial insulin resistance in human obesity

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dc.contributor.authorKarki, S.
dc.contributor.authorFarb, M.
dc.contributor.authorNgo, D.
dc.contributor.authorMyers, S.
dc.contributor.authorPuri, V.
dc.contributor.authorHamburg, N.
dc.contributor.authorCarmine, B.
dc.contributor.authorHess, D.
dc.contributor.authorGokce, N.
dc.date.issued2015
dc.description.abstractObjective: Increased visceral adiposity has been closely linked to insulin resistance, endothelial dysfunction, and cardiometabolic disease in obesity, but pathophysiological mechanisms are poorly understood. We sought to investigate mechanisms of vascular insulin resistance by characterizing depot-specific insulin responses and gain evidence that altered functionality of transcription factor forkhead box O-1 (FOXO-1) may play an important role in obesity-related endothelial dysfunction. Approach and Results: We intraoperatively collected paired subcutaneous and visceral adipose tissue samples from 56 severely obese (body mass index, 43 ± 7 kg/m²) and 14 nonobese subjects during planned surgical operations, and characterized depot-specific insulin-mediated responses using Western blot and quantitative immunofluorescence techniques. Insulin signaling via phosphorylation of FOXO-1 and consequent endothelial nitric oxide synthase stimulation was selectively impaired in the visceral compared with subcutaneous adipose tissue and endothelial cells of obese subjects. In contrast, tissue actions of insulin were preserved in nonobese individuals. Pharmacological antagonism with AS1842856 and biological silencing using small interfering RNA-mediated FOXO-1 knockdown reversed insulin resistance and restored endothelial nitric oxide synthase activation in the obese. Conclusions: We observed profound endothelial insulin resistance in the visceral adipose tissue of obese humans which improved with FOXO-1 inhibition. FOXO-1 modulation may represent a novel therapeutic target to diminish vascular insulin resistance. In addition, characterization of endothelial insulin resistance in the adipose microenvironment may provide clues to mechanisms of systemic disease in human obesity.
dc.description.statementofresponsibilityShakun Karki, Melissa G. Farb, Doan T.M. Ngo, Samantha Myers, Vishwajeet Puri, Naomi M. Hamburg, Brian Carmine, Donald T. Hess, Noyan Gokce
dc.identifier.citationArteriosclerosis, Thrombosis, and Vascular Biology, 2015; 35(6):1498-1506
dc.identifier.doi10.1161/ATVBAHA.114.305139
dc.identifier.issn1079-5642
dc.identifier.issn1524-4636
dc.identifier.urihttp://hdl.handle.net/2440/116121
dc.language.isoen
dc.publisherAmerican Heart Association
dc.rights© 2015 American Heart Association, Inc.
dc.source.urihttps://doi.org/10.1161/atvbaha.114.305139
dc.subjectFOXO1 protein, human; insulin; nitric oxide synthase type III; obesity
dc.titleForkhead box O-1 modulation improves endothelial insulin resistance in human obesity
dc.typeJournal article
pubs.publication-statusPublished

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