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

Greg W Trieger; Ariane R Pessentheiner; Sean C Purcell; Courtney R Green; Natalie DeForest; Karl Willert; Amit R Majithia; Christian M Metallo; Kamil Godula; Philip L S M Gordts

doi:10.1016/j.jbc.2023.104611

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

J Biol Chem. 2023 May;299(5):104611. doi: 10.1016/j.jbc.2023.104611. Epub 2023 Mar 15.

Authors

Affiliations

¹ Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA.
² Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA.
³ Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA.
⁴ Department of Bioengineering, University of California, San Diego, La Jolla, California, USA.
⁵ Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California, USA.
⁶ Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA; Department of Pediatrics, University of California, San Diego, La Jolla, California, USA.
⁷ Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, California, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA. Electronic address: kgodula@ucsd.edu.
⁸ Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California, USA; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA. Electronic address: pgordts@health.ucsd.edu.

Abstract

Adipose tissue plays a crucial role in maintaining metabolic homeostasis by storing lipids and glucose from circulation as intracellular fat. As peripheral tissues like adipose tissue become insulin resistant, decompensation of blood glucose levels occurs causing type 2 diabetes (T2D). Currently, modulating the glycocalyx, a layer of cell-surface glycans, is an underexplored pharmacological treatment strategy to improve glucose homeostasis in T2D patients. 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 pre-adipocytes 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.

Keywords: Wnt signaling; adipocyte; glucose; heparan sulfate; proteoglycan.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adipogenesis* / genetics
Diabetes Mellitus, Type 2* / drug therapy
Diabetes Mellitus, Type 2* / metabolism
Glucose / metabolism
Glycocalyx / metabolism
Heparitin Sulfate
Humans

Substances

Heparitin Sulfate
Glucose

Abstract

Publication types

MeSH terms

Substances

Grants and funding