Tetrahydrobiopterin activates brown adipose tissue and regulates systemic energy metabolism
Tetrahydrobiopterin activates brown adipose tissue and regulates systemic energy metabolism
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DOI：
10.1172/jci.insight.91981
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发表时间：
2017-05-04
期刊：
影响因子：
8
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
--
作者：
Oguri, Yasuo;Fujita, Yoshihito;Inagaki, Nobuya
棕色脂肪组织(BAT)是增加能量消耗的中枢器官，其调节因子可用于临床治疗肥胖症。四氢生物蝶呤(BH4)是酪氨酸羟化酶和一氧化氮合酶(NOS)的重要辅因子。虽然BH4可以调节已知的BAT调节因子，如去甲肾上腺素(NA)和NO，但BH4对BAT功能的参与尚不清楚。在本研究中，我们研究了BH4在BAT调节中的作用。HPH-1小鼠是BH4缺乏的小鼠模型，表现为肥胖、肥胖、糖耐量异常、胰岛素抵抗和BAT功能受损。通过将BAT从BH4充足的小鼠(对照小鼠)移植到BH4缺乏的小鼠身上，受损的BAT功能和全身代谢紊乱都得到了改善，强烈表明BH4诱导的BAT在调节全身能量代谢中起着关键作用。交感神经来源的NA和血管内皮细胞来源的NO均参与BH4的调节。此外，BH4通过NO对棕色脂肪细胞的刺激有直接作用。总而言之，BH4激活BAT并调节全身能量代谢；这表明一种治疗代谢紊乱的方法，如肥胖症和糖尿病。
Brown adipose tissue (BAT) is a central organ that acts to increase energy expenditure; its regulatory factors could be clinically useful in the treatment of obesity. Tetrahydrobiopterin (BH4) is an essential cofactor of tyrosine hydroxylase and nitric oxide synthase (NOS). Although BH4 regulates the known regulatory factors of BAT, such as noradrenaline (NA) and NO, participation of BH4 in BAT function remains unclear. In the present study, we investigate the role of BH4 in the regulation of BAT. Hph-1 mice, a mouse model of BH4 deficiency, exhibit obesity, adiposity, glucose intolerance, insulin resistance, and impaired BAT function. Impaired BAT function was ameliorated together with systemic metabolic disturbances by BAT transplantation from BH4-sufficient mice (control mice) into BH4-deficient mice, strongly suggesting that BH4-induced BAT has a critical role in the regulation of systemic energy metabolism. Both NA derived from the sympathetic nerve and NO derived from endothelial NOS in the blood vessels participate in the regulation of BH4. In addition, a direct effect of BH4 in the stimulation of brown adipocytes via NO is implicated. Taken together, BH4 activates BAT and regulates systemic energy metabolism; this suggests an approach for metabolic disorders, such as obesity and diabetes.