Adipose tissue heparan sulfate proteoglycans – critical regulators of adipocyte metabolism and glucose homeostasis

Abstract

Heparan sulfate (HS) proteoglycans are important components of cells and the extracellular microenvironment. Interaction between growth factors and receptors is often modulated by the amount and degree of HS sulfation. We hypothesize that natural variation in HS composition on adipocytes serves as a rheostat for adipocyte function and impacts susceptibility to develop insulin resistance, type‐2 diabetes and obesity.We use mice with adipose tissue (AT) specific inactivation of the HS biosynthetic enzymes N‐acetylglucosamine‐N‐deacetylase‐N‐sulfotransferase 1 (Ndst1‐AKO) and Exostosin 1 (Ext1‐AKO) mediated by the Adipoq‐Cre driver. These models allow us to study the impact of HS sulfation and chain length, respectively, on adipocyte metabolism and systemic glucose homeostasis in the context of diet‐induced obesity.On a high fat diet both Ndst1‐AKO and Ext1‐AKO mice gain more weight compared to WT littermates and develop significant glucose intolerance and insulin resistance. A pyruvate tolerance test indicates that disturbed adipocyte‐HS significantly affects liver gluconeogenesis. Moreover, hepatic inflammation is elevated in Ndst1‐AKO mice compared to WT controls, indicating that adipocyte‐HS also influences the organ cross‐talk between AT and liver. Previously, it has been shown that fibroblast growth factor 1 (FGF1) is a potent insulin sensitizer with great therapeutic potential. FGF1 signaling depends on the presence of HS on the plasma membrane. We show that the insulin‐sensitizing effect of FGF1 is diminished in Ndst1‐AKO and Ext1‐AKO mice. However, the insulin sensitization response to FGF21, another metabolic active FGF without HS‐dependency, is unaffected by HS alterations in AT.Our data suggest that HS composition in AT regulates FGF1 sequestration and signaling, leading to metabolic complications upon diet‐induced obesity. In this context, our results underline the importance of HS composition in AT for signaling processes that are critical for glucose homeostasis.