Reduction of Liver Heparan Sulfate Proteoglycans Promotes Endocrine Benefits of Therapeutic FGF1

Abstract

Type‐2 diabetes, a is a global epidemic that currently drives an enormous health and economic burden. The disease is chronic condition in which blood glucose levels are deregulated due to insulin resistant in metabolic tissues, such as liver, muscle and adipose tissue. Recently, fibroblast growth factor 1 (FGF1) has been implicated in promoting insulin‐depended glucose uptake in adipose tissue. Therefore, FGF1 is being considered for therapeutic use in type‐2 diabetes patients.Typically, both FGF and FGF Receptors (FGFR) bind heparan sulfate proteoglycans (HSPGs).This multimetric FGF‐FGFR interaction with HSPGs promotes stable complex formation allowing robust intracellular signaling. Our preliminary results show that the degree of HSPG sulfation in adipose tissue is critical for FGF1 mediated glucose lowering. The liver expresses significant amounts of FGFRs and highly sulfated cell surface HSPGs. Therefore, we hypothesize that the liver is a prime scavenger of therapeutic FGF1 reducing its partitioning to FGFR in adipose tissue and consequently its therapeutic window.To address this hypothesis, we made use of wildtype and genetically modified mice with reduced liver HSPG sulfation introduced by liver specific inactivation of one of the biosynthetic enzymes N‐deacetylase and N‐sulfotransferase 1 (NDST1; Ndst1f/fAlbCre+). Both mice were fed a 60% kcal high fat diet (HFD) to initiate diet‐induced obesity and the associated peripheral insulin resistance. Throughout the HFD treatment, we monitored the mice’s glucose and body weight on a biweekly basis and found no phenotypic changes between the wildtype Ndst1f/fAlbCre+ mice. After 10 weeks on the HFD, we tested each mice group’s insulin and glucose tolerance via injections of the corresponding substrates and saw no significant differences in glucose homeostasis. By week 15 of HFD feeding, we injected a single dose of recombinant FGF1 protein (0.5 mg/kg) and recorded the FGF1‐induced glucose lowering in periodic intervals following the injection. Ndst1f/fAlbCre+ mice presented with a greater reduction in FGF1‐induced glucose lowering as well as longer lasting reduction effect.Overall, the results from this research will provide an enhanced understanding of FGF1 and HSPGs that could contribute to future studies and treatments of type‐2 diabetes and overall help increase the therapeutic window of FGF1 treatment in type‐2 diabetes.Support or Funding InformationHave been awarded Undergraduate Research Scholarship grant for working as a full‐time researcher during a 10‐week period.