Importance of Heparan Sulfate in Adipose Tissue

[Speaker] Takuro Matsuzawa:1
[Co-author] Takeo Yoshikawa:1, Kazuhiko Yanai:1
1:Pharmacology, Tohoku University Graduate School of Medicine, Japan

Heparan sulfate (HS) is a highly sulfated glycosaminoglycan distributed on the cell surface and in the extracellular matrix. HS is involved in diverse biological events including embryonic development, angiogenesis and tumor metastasis. Recent studies revealed that lack of HS induced autism-like behaviors and chondrosarcoma, indicating the pathophysiological involvement of HS in various disorders. Moreover, in previous study, we revealed that HS in pancreatic β-cells maintained glucose homeostasis with regulating insulin secretion. This study indicated that HS plays important roles in glucose metabolism. Adipocyte is also important tissue which involves in glucose metabolism, and adipocyte expresses HS. However, the roles of HS in adipocyte remained to be elucidated.
First, we evaluated the roles of HS in differentiation using 3T3-L1 cells. The expression levels of Ext1 (synthesis enzyme of HS) were elevated with differentiation. Lipid droplet and the expression levels of PPARγ (a differentiation marker) were decreased in differentiation after heparitinase (degradation enzyme of HS) treatment. These results indicated Ext1 and HS are essential in differentiation. Next, we generated white adipocyte (WAT) specific Ext1-deficient mice (cKO) to analyze the importance of HS in WAT. Body weight of cKO was significantly reduced compared to that of control mice (control). Amount of food intake was increasing tendency in cKO. Blood glucose levels in fasted state were normal. cKO, however, exhibited glucose intolerance after glucose challenge. Plasma insulin levels after glucose challenge were increased in cKO and cKO showed insulin resistance after insulin challenge. These results indicated cKO showed glucose intolerance due to insulin resistance. RT-PCR analysis showed the expression levels of KLF15, PPARγ and FABP4 (differentiation marker) were decreased in cKO. Plasma leptin level was also decreased in cKO. These date indicated that HS is essential for normal differentiation, and regulates glucose metabolism by maturing WAT.

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