Combined deletion of Y1, Y2, and Y4 receptors prevents hypothalamic neuropeptide Y overexpression-induced hyperinsulinemia despite persistence of hyperphagia and obesity
Combined deletion of Y1, Y2, and Y4 receptors prevents hypothalamic neuropeptide Y overexpression-induced hyperinsulinemia despite persistence of hyperphagia and obesity
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DOI：
10.1210/en.2006-0097
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发表时间：
2006-11-01
期刊：
影响因子：
4.8
通讯作者：
Herzog, Herbert
中科院分区：
文献类型：
--
作者：
Lin, En-Ju D.;Sainsbury, Amanda;Herzog, Herbert
神经肽Y(NPY)是能量稳态的关键调节因子，与肥胖和2型糖尿病的发生有关。虽然众所周知，下丘脑注射外源性神经肽Y肽会导致体重增加、吞噬功能亢进以及肥胖综合征特有的许多激素和代谢变化，但介导这些影响的Y受体(S)仍存在争议和不清楚。为了探讨不同Y受体在NPY诱导的肥胖综合征中的作用，我们使用重组腺相关病毒载体在选择性单一或多个Y受体(包括Y1、Y2和Y4)缺陷的小鼠中过表达NPY。这项研究的结果表明，长期下丘脑NPY的过度表达会导致明显的吞噬功能亢进、性腺功能低下、体重增加、脂肪组织堆积增加、高胰岛素血症以及其他肥胖综合征特有的激素变化。NPY诱导的吞噬功能亢进、性腺功能低下和肥胖综合征在所有被研究的基因型鼠(Y1(-/-)、Y2(-/-)、Y2Y4(-/-)和Y1Y2Y4(-/-)小鼠)中持续存在。然而，Y1、Y2和Y4受体的三重缺失可以预防NPY诱导的高胰岛素血症。这些发现表明，在这种情况下，Y1、Y2和Y4受体并不是NPY的高吞噬、低性腺和肥胖效应的关键因素，但它们负责NPY对循环胰岛素水平的中枢调节。
Neuropeptide Y (NPY) is a key regulator of energy homeostasis and is implicated in the development of obesity and type 2 diabetes. Whereas it is known that hypothalamic administration of exogenous NPY peptides leads to increased body weight gain, hyperphagia, and many hormonal and metabolic changes characteristic of an obesity syndrome, the Y receptor(s) mediating these effects is disputed and unclear. To investigate the role of different Y receptors in the NPY-induced obesity syndrome, we used recombinant adeno-associated viral vector to overexpress NPY in mice deficient of selective single or multiple Y receptors (including Y1, Y2, and Y4). Results from this study demonstrated that long-term hypothalamic overexpression of NPY lead to marked hyperphagia, hypogonadism, body weight gain, enhanced adipose tissue accumulation, hyperinsulinemia, and other hormonal changes characteristic of an obesity syndrome. NPY-induced hyperphagia, hypogonadism, and obesity syndrome persisted in all genotypes studied (Y1(-/-), Y2(-/-), Y2Y4(-/-), and Y1Y2Y4(-/-) mice). However, triple deletion of Y1, Y2, and Y4 receptors prevented NPY-induced hyperinsulinemia. These findings suggest that Y1, Y2, and Y4 receptors under this condition are not crucially involved in NPY's hyperphagic, hypogonadal, and obesogenic effects, but they are responsible for the central regulation of circulating insulin levels by NPY.