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bioRxiv · 10.1101/2021.07.08.451710

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

Trieger, G.·Pessentheiner, A.·Purcell, S.·Green, C. R.·DeForest, N.·Willert, K.·Majithia, A.·Metallo, C.·Godula, K.·Gordts, P.
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Abstract

Adipose tissue (AT) plays a crucial role in maintaining me tabolic 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. SIGNIFICANCEMetabolic disorders associated with the Western-style diet, such as type 2 diabetes, are among the main drivers of mortality in the US and globally, with more than 380 million people currently affected by this disease worldwide. However, treatment options for type 2 diabetes are currently limited to management of caloric uptake and expenditure, with none able to reverse the condition long-term. The ability to reprogram adipose tissues to improve their overall capacity to clear glucose may provide one such opportunity. Here we provide evidence that glycocalyx remodeling in pre-adipocytes with heparan sulfate mimetics will alter their differentiation program by modulating Wnt signaling to produce adipocytes with increased glucose uptake and utilization.

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Trieger, G., Pessentheiner, A., Purcell, S., Green, C. R., DeForest, N., Willert, K., Majithia, A., Metallo, C., Godula, K., Gordts, P.. 2021-07-09. Glycocalyx engineering with heparan sulfate mimetics attenuates Wnt activity during adipogenesis to promote glucose uptake and metabolism.. https://doi.org/10.1101/2021.07.08.451710

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