214-OR: Increases in TUG Abundance and Expression Are a Feature of Insulin-Resistant Human Adipose Tissue

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Introduction and Objective: White adipose tissue (WAT) insulin resistance (IR) is essential to the pathogenesis of metabolic disease; yet defects in human WAT insulin signaling are not well characterized. This study elucidates alterations to WAT insulin signaling associated with human IR.Methods: Human WAT was obtained from three cohorts of patients with obesity: 1) in a bariatric surgery cohort (RESOLVE), RNASeq was performed on WAT collected before and after weight loss; 2) in another cohort (SODA), glucose or fructose-sweetened beverages were given before WAT collection and proteomics analyses were performed; 3) in an adolescent cohort, immunoblotting and qPCR assessed WAT biopsied before or during hyperinsulinemic euglycemic clamps.Results: Attenuation of insulin-stimulated AKT phosphorylation in IR vs. relatively insulin sensitive (IS) adolescents was not significant (IR vs IS: -37.6%, p>0.1). Expectedly, GLUT4 decreased in IR (Resolve: log PC = -1.54, p<0.000000001; SODA: R2=0.367, p<0.05; Adolescent: -60.3%, p<0.05). TUG, which traps insulin-responsive GLUT4, was increased in IR (Resolve: log PC +0.39, p<0.05; SODA: R2=0.277, p<0.05; Adolescent: +48.5%, p<0.01). Gene expression throughout the TC10 pathway that mediates insulin-stimulated TUG cleavage was changed pre- versus post- bariatric surgery in the RESOLVE study. A subset of TC10 pathway proteins also changed in the SODA and Adolescent studies.Conclusion: In three cohorts, IR is correlated with increased WAT TUG. As well, molecular regulation of TC10 pathway is altered, underscoring the importance of TUG regulation to WAT metabolic health. As one of the first descriptions of altered signaling by this pathway in human WAT, this data can drive future therapeutics for patients with metabolic disease.

Disclosure

J.W. Strober: None. K.W. ter Horst: None. A. Slusher: None. J.A. Paulo: None. B. Gassaway: None. S. Shuken: None. S. Caprio: None. M. Serlie: None. J. Bogan: None. D.F. Vatner: None.

Funding

National Institutes of Health (DK124272); National Institutes of Health (DK007058)



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