Heparan sulfate promotes differentiation of white adipocytes to maintain insulin sensitivity and glucose homeostasis

Takuro Matsuzawa, Masanobu Morita, Ai Shimane, Rina Otsuka, Yu Mei, Fumitoshi Irie, Yu Yamaguchi, Kazuhiko Yanai, Takeo Yoshikawa

Research output: Contribution to journalArticlepeer-review

Abstract

Heparan sulfate (HS), a highly sulfated linear polysaccharide, is involved in diverse biological functions in various tissues. Although previous studies have suggested a possible contribution of HS to the differentiation of white adipocytes, there has been no direct evidence supporting this. Here, we inhibited the synthesis of HS chains in 3T3-L1 cells using CRISPR–Cas9 technology, resulting in impaired differentiation of adipocytes with attenuated bone morphogenetic protein 4 (BMP4)–fibroblast growth factor 1 (FGF1) signaling pathways. HS reduction resulted in reduced glucose uptake and decreased insulin-dependent intracellular signaling. We then made heterozygous mutant mice for the Ext1 gene, which encodes an enzyme essential for the HS biosynthesis, specifically in the visceral white adipose tissue (Fabp4-Cre+::Ext1flox/WT mice, hereafter called Ext1Δ/WT) to confirm the importance of HS in vivo. The expression levels of transcription factors that control adipocyte differentiation, such as peroxisome proliferator–activated receptor gamma, were reduced in Ext1Δ/WT adipocytes, which contained smaller, unilocular lipid droplets, reduced levels of enzymes involved in lipid synthesis, and altered expression of BMP4–FGF1 signaling molecules. Furthermore, we examined the impact of HS reduction in visceral white adipose tissue on systemic glucose homeostasis. We observed that Ext1Δ/WT mice showed glucose intolerance because of insulin resistance. Our results demonstrate that HS plays a crucial role in the differentiation of white adipocytes through BMP4–FGF1 signaling pathways, thereby contributing to insulin sensitivity and glucose homeostasis.

Original languageEnglish
Article number101006
JournalJournal of Biological Chemistry
Volume297
Issue number3
DOIs
Publication statusPublished - 2021 Sep 1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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