Glycocalyx engineering with heparan sulfate mimetics attenuates Wnt activity during adipogenesis to promote glucose uptake and metabolism

Abstract

Adipose tissue (AT) plays a crucial role in maintaining metabolic homeostasis by storing lipids and glucose from circulation as intracellular fat. As peripheral tissues like AT become insulin resistant, decompensation of blood glucose levels occurs causing type 2 diabetes (T2D). Currently, glycocalyx modulating as a pharmacological treatment strategy to improve glucose homeostasis in T2D patients is underexplored. Here, we show a novel role for cell surface heparan sulfate (HS) in establishing glucose uptake capacity and metabolic utilization in differentiated adipocytes. Using a combination of chemical and genetic interventions, we identified that HS modulates this metabolic phenotype by attenuating levels of Wnt signaling during adipogenesis. By engineering the glycocalyx of preadipocytes with exogenous synthetic HS mimetics, we were able to enhance glucose clearance capacity after differentiation through modulation of Wnt ligand availability. These findings establish the cellular glycocalyx as a possible new target for therapeutic intervention in T2D patients by enhancing glucose clearance capacity independent of insulin secretion.

Publication
Journal of Biological Chemistry, March 2023