Altered Molecular Regulation of TUG Is a Central Feature of Insulin-Resistant Human Adipose Tissue

White adipose tissue (WAT) insulin resistance (IR) is a central feature of metabolic syndrome; however, data regarding defects in WAT insulin signaling in humans with IR is limited. To determine which defects in WAT insulin signaling are associated with human IR, WAT was obtained from three cohorts of patients with obesity. In a bariatric surgery cohort (RESOLVE), subcutaneous WAT (n = 24) was collected before and after weight loss, and RNA sequencing was performed. In another bariatric surgery cohort (SODA), glucose- or fructose-sweetened beverages were consumed before subcutaneous and omental WAT collection, and proteomic data were collected (n = 16). In an adolescent cohort, subcutaneous WAT (n = 14) was collected before and during hyperinsulinemic clamps, and both quantitative PCR and immunoblotting were performed. The TC10–tether containing a UBX domain for GLUT4 (TUG) pathway regulates GLUT4 translocation and glucose uptake in insulin-responsive tissues. Expectedly, in the adipose tissue from all three cohorts, GLUT4 content decreased in those with IR. TUG, which traps insulin-responsive GLUT4 vesicles in intracellular pools, was increased in the setting of IR in all three cohorts. Furthermore, expression of multiple components of the TC10–TUG pathway was altered with IR. Therefore, human WAT IR is characterized by altered molecular regulation of the TC10–TUG pathway, underscoring the importance of this pathway to WAT metabolic health.

There is a paucity of data regarding defects in insulin signaling in insulin-resistant human white adipose tissue (WAT). The tether containing a UBX domain for GLUT4 (TUG) protein, which retains GLUT4 vesicles, was increased in WAT of participants with greater insulin resistance in three different cohorts with obesity. Components of the TUG regulatory signaling pathway were differentially expressed between participants with greater insulin resistance and those with greater insulin sensitivity. TUG may provide an important pharmacologic target in the treatment or prevention of metabolic dysfunction in patients with obesity.