Abstract 15894: Vascular Insulin Signaling Mediated by Forkhead Box Protein O1 is Impaired in Visceral Adipose Tissue
Background: Increased visceral adiposity has been closely linked to insulin resistance and cardiometabolic risk. We have previously demonstrated upregulation of a pro-inflammatory transcriptome and endothelial dysfunction of the visceral microvaculature in human obesity. In this present study, we sought to investigate mechanisms of obesity-related insulin resistance by characterizing adipose depot-specific microvascular responses to insulin, and gain evidence that altered functionality of transcription factor forkhead box protein O1 (FOXO1) may play an important role in vascular insulin resistance.
Methods and Results: We intra-operatively collected subcutaneous and visceral adipose tissue in 25 obese subjects (age 42±11 years, BMI 43±5 kg/m2) during planned bariatric surgery. Insulin-mediated, endothelium-dependent vasodilation of adipose tissue arterioles assessed by videomicroscopy was significantly impaired in visceral compared to subcutaneous fat (area under the curve: -5 ± 9 vs. 40 ± 23 au, p<0.05). mRNA expression quantified by RT-PCR relevant to the insulin signaling cascade including insulin receptor (p<0.05), insulin receptor substrate 1 (p<0.01), Akt (p<0.001), and FOXO1 (p<0.001) were significantly downregulated in visceral compared to subcutaneous fat. In endothelial cells isolated from the same adipose tissue regions, using quantitative immunofluorescence we demonstrated that insulin-mediated activation of endothelial nitric oxide synthase (eNOS) at serine-1177 was markedly reduced in endothelial cells isolated from visceral compared to subcutaneous fat (p<0.05). Additionally, endothelial cells isolated from subcutaneous adipose tissue displayed intact FOXO1 phosphorylation at serine-256, while this response was blunted in the visceral depot (p<0.05).
Conclusion: We demonstrate evidence of profound vascular insulin resistance in visceral adipose arterioles associated with the novel finding of impaired FOXO1 signaling in vascular endothelial cells. Characterization of endothelial insulin resistance in the adipose microenvironment may provide clues to mechanisms of systemic insulin resistance in human obesity.
- © 2013 by American Heart Association, Inc.