Institute for Molecular Science of Medicine, Aichi Medical University, Nagakute, Aichi, Japan.
Glycobiology. 2013 Aug;23(8):980-92. doi: 10.1093/glycob/cwt037. Epub 2013 May 20.
Here, we report that male heparan sulfate 6-O-sulfotransferase-2 (Hs6st2) knockout mice showed increased body weight in an age-dependent manner even when fed with a normal diet and showed a phenotype of impaired glucose metabolism and insulin resistance. Quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis showed that the expression of mitochondrial uncoupling proteins Ucp1 and Ucp3 was reduced in the interscapular brown adipose tissue (BAT) of male Hs6st2 knockout mice, suggesting reduced energy metabolism. The serum level of thyroid-stimulating hormone was significantly higher and that of thyroxine was lower in the knockout mice. When cultures of brown adipocytes from wild-type and Hs6st2 knockout mice isolated and differentiated in vitro were treated with FGF19 (fibroblast growth factor 19) or FGF21 in the presence or the absence of heparitinase I, phosphorylation of p42/p44 mitogen-activated protein (MAP) kinase was reduced. Heparan sulfate (HS) 6-O-sulfation was reduced not only in BAT but also in the thyroid tissue of the knockout mice. Thus, 6-O-sulfation in HS seems to play an important role in mediating energy metabolism by controlling thyroid hormone levels and signals from the FGF19 subfamily proteins, and the alteration of the HS composition may result in metabolic syndrome phenotypes such as altered glucose and insulin tolerance.
在这里，我们报告说，雄性肝素硫酸 6-O-磺基转移酶-2（Hs6st2）敲除小鼠即使在正常饮食喂养的情况下，其体重也会随着年龄的增长而增加，表现出葡萄糖代谢受损和胰岛素抵抗的表型。定量逆转录聚合酶链反应（RT-PCR）分析表明，雄性 Hs6st2 敲除小鼠肩胛间棕色脂肪组织（BAT）中解偶联蛋白 Ucp1 和 Ucp3 的表达减少，提示能量代谢减少。敲除小鼠的血清促甲状腺激素水平显著升高，甲状腺素水平降低。当从野生型和 Hs6st2 敲除小鼠中分离并体外分化的棕色脂肪细胞培养物在存在或不存在肝素酶 I 的情况下用 FGF19（成纤维细胞生长因子 19）或 FGF21 处理时，p42/p44 丝裂原激活蛋白（MAP）激酶的磷酸化减少。HS6-O-硫酸化不仅在 BAT 中减少，而且在敲除小鼠的甲状腺组织中也减少。因此，HS 中的 6-O-硫酸化似乎通过控制甲状腺激素水平和 FGF19 亚家族蛋白的信号来发挥调节能量代谢的重要作用，HS 组成的改变可能导致代谢综合征表型，如葡萄糖和胰岛素耐量改变。
