| First Author | Matsuzawa T | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 3 | Pages | 101006 |
| PubMed ID | 34310946 | Mgi Jnum | J:338711 |
| Mgi Id | MGI:6818316 | Doi | 10.1016/j.jbc.2021.101006 |
| Citation | Matsuzawa T, et al. (2021) Heparan sulfate promotes differentiation of white adipocytes to maintain insulin sensitivity and glucose homeostasis. J Biol Chem 297(3):101006 |
| abstractText | 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(+)::Ext1(flox/WT) mice, hereafter called Ext1(Delta/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 Ext1(Delta/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 Ext1(Delta/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. |
