Yang Liang, Scott Karen A, Hyun Jayson, Tamashiro Kellie L, Tray Nancy, Moran Timothy H, Bi Sheng
Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
J Neurosci. 2009 Jan 7;29(1):179-90. doi: 10.1523/JNEUROSCI.4379-08.2009.
Previous studies have suggested that neuropeptide Y (NPY) in the dorsomedial hypothalamus (DMH) serves as an important signaling peptide in the regulation of energy balance. To elucidate such actions, we used the adenoassociated virus (AAV) system to alter Npy gene expression in the DMH and examined the effects of these alterations on food intake and energy balance as well as explored its downstream signaling pathway. We found that AAV-mediated overexpression of NPY in the DMH of lean rats increased food intake and body weight, and exacerbated high-fat diet-induced obesity. Knockdown of NPY expression in the DMH via AAV-mediated RNA interference ameliorated the hyperphagia, obesity, and diabetes of Otsuka Long-Evans Tokushima Fatty (OLETF) rats. NPY knockdown in the DMH produced a nocturnal and meal size-specific feeding effect. Moreover, we found that knockdown of DMH NPY expression in intact rats reduced NPY content in the nucleus of the solitary tract (NTS) and the dorsal motor nucleus of the vagus and affected within-meal satiation. DMH NPY knockdown increased the feeding inhibitory and NTS c-Fos responses to peripheral administration of cholecystokinin. Together, these results indicate that DMH NPY plays an important role in modulating food intake and energy balance and its dysregulation causes disordered energy balance leading to obesity.
先前的研究表明，下丘脑背内侧核（DMH）中的神经肽Y（NPY）在能量平衡调节中作为一种重要的信号肽发挥作用。为了阐明这种作用，我们使用腺相关病毒（AAV）系统来改变DMH中Npy基因的表达，并研究这些改变对食物摄入和能量平衡的影响，同时探索其下游信号通路。我们发现，AAV介导的在瘦大鼠DMH中过表达NPY会增加食物摄入量和体重，并加剧高脂饮食诱导的肥胖。通过AAV介导的RNA干扰敲低DMH中的NPY表达可改善大冢长- Evans 德岛肥胖（OLETF）大鼠的食欲亢进、肥胖和糖尿病。DMH中NPY的敲低产生了夜间和特定餐量的进食效应。此外，我们发现，在完整大鼠中敲低DMH中的NPY表达会降低孤束核（NTS）和迷走神经背运动核中的NPY含量，并影响餐内饱腹感。敲低DMH中的NPY会增加对胆囊收缩素外周给药的进食抑制和NTS c-Fos反应。总之，这些结果表明，DMH中的NPY在调节食物摄入和能量平衡中起重要作用，其失调会导致能量平衡紊乱，进而导致肥胖。
