Ruohonen Suvi T, Pesonen Ullamari, Moritz Niko, Kaipio Katja, Röyttä Matias, Koulu Markku, Savontaus Eriika
Department of Pharmacology, Drug Development and Therapeutics, University of Turku, Turku, Finland.
Diabetes. 2008 Jun;57(6):1517-25. doi: 10.2337/db07-0722. Epub 2008 Feb 14.
A functional polymorphism leucine 7 proline in the human neuropeptide Y (NPY) gene leading to increased NPY release from sympathetic nerves is associated with traits of metabolic syndrome. Although hypothalamic NPY neurons play an established role in promoting positive energy balance, the role of NPY colocalized with norepinephrine in sympathetic nervous system and brain noradrenergic neurons remains obscure.
To clarify the role of NPY in noradrenergic neurons, we generated a transgenic mouse overexpressing NPY under dopamine-beta-hydroxylase promoter and characterized the metabolic phenotype of the OE-NPY(DbetaH) mouse.
NPY levels are increased by 1.3-fold in adrenal glands and 1.8-fold in the brainstem but not in the hypothalamus in OE-NPY(DbetaH) mice. They display increased white adipose tissue mass and cellularity and liver triglyceride accumulation without hyperphagia or increased body weight. Hyperinsulinemia and impaired glucose tolerance develop by the age of 6 months in the OE-NPY(DbetaH) mice. Furthermore, circulating ghrelin is significantly increased in comparison with wild-type mice.
The present study shows that even a moderate increase in NPY levels in noradrenergic neurons leads to disturbances in glucose and lipid metabolism. The OE-NPY(DbetaH) mouse is an interesting new model to investigate the pathophysiology of some key components of the cluster of abnormalities characterizing the metabolic syndrome.
人类神经肽Y（NPY）基因中的一个功能性多态性位点亮氨酸7脯氨酸导致交感神经释放NPY增加，这与代谢综合征的特征相关。尽管下丘脑NPY神经元在促进正能量平衡方面已确立其作用，但NPY与去甲肾上腺素共定位在交感神经系统和脑去甲肾上腺素能神经元中的作用仍不清楚。
为了阐明NPY在去甲肾上腺素能神经元中的作用，我们构建了一种在多巴胺-β-羟化酶启动子控制下过表达NPY的转基因小鼠，并对OE-NPY（DβH）小鼠的代谢表型进行了表征。
在OE-NPY（DβH）小鼠中，肾上腺NPY水平增加1.3倍，脑干中增加1.8倍，但下丘脑未增加。它们表现出白色脂肪组织量和细胞数量增加以及肝脏甘油三酯蓄积，而没有食欲亢进或体重增加。OE-NPY（DβH）小鼠在6月龄时出现高胰岛素血症和糖耐量受损。此外，与野生型小鼠相比，循环中的胃饥饿素显著增加。
本研究表明，即使去甲肾上腺素能神经元中NPY水平适度增加也会导致糖脂代谢紊乱。OE-NPY（DβH）小鼠是一种有趣的新模型，可用于研究代谢综合征特征性异常集群中一些关键成分的病理生理学。
