AgRP Innervation onto POMC Neurons Increases with Age and Is Accelerated with Chronic High-Fat Feeding in Male Mice
AgRP Innervation onto POMC Neurons Increases with Age and Is Accelerated with Chronic High-Fat Feeding in Male Mice
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DOI：
10.1210/en.2012-1643
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发表时间：
2013-01-01
期刊：
影响因子：
4.8
通讯作者：
Xu, Allison W.
中科院分区：
文献类型：
--
作者：
Newton, A. Jamila;Hess, Simon;Xu, Allison W.
在许多哺乳动物中，体重在整个成年期持续增加，直到中年晚期。激素瘦素是维持体重所必需的，因为高水平的瘦素促进负能量平衡。然而，随着动物年龄的增长，它们体重的增加伴随着循环中瘦素水平的稳步上升，这表明对抗瘦素的致癌作用的反调节机制的逐步发展。下丘脑神经元共表达刺豚鼠相关肽（AgRP）和神经肽Y是瘦素的直接靶点。这些神经元促进正能量平衡，并且它们通过直接神经肽作用和γ-氨基丁酸的释放来抑制促肾上腺皮质激素原性阿黑皮素（POMC）神经元。我们在这里表明，AgRP和神经肽Y invervation到POMC神经元显着增加，随着年龄的雄性小鼠。这与抑制性突触后电流的进行性增加和POMC放电率随年龄的降低有关。接受高密度AgRP斑点的POMC神经元的神经元活性显著减弱。这些高密度的AgRP输入与正常小鼠中的瘦素水平相关，并且在缺乏瘦素的小鼠中几乎不存在。在高瘦素血症、饮食诱导的肥胖小鼠中，增加的AgRP神经支配到POMC胞体的进展加速。总之，我们的研究表明，下丘脑AgRP神经支配的调制构成了一种机制，以对抗与年龄相关的瘦素水平上升的影响，从而维持体重和脂肪量在成年后的水平升高。（内分泌学154：172-183，2013）
In many mammals, body weight increases continuously throughout adulthood until late middle age. The hormone leptin is necessary for maintaining body weight, in that high levels of leptin promote negative energy balance. As animals age, however, their increase in body weight is accompanied by a steady rise in circulating leptin levels, indicating the progressive development of counterregulatory mechanisms to antagonize leptin's anorexigenic effects. Hypothalamic neurons coexpressing agouti-related peptide (AgRP) and neuropeptide Y are direct leptin targets. These neurons promote positive energy balance, and they inhibit anorexigenic proopiomelanocortin (POMC) neurons via direct neuropeptide action and release of gamma-aminobutyric acid. We show here that AgRP and neuropeptide Y innvervation onto POMC neurons increases dramatically with age in male mice. This is associated with progressive increase of inhibitory postsynaptic currents and decrease of POMC firing rate with age. Neuronal activity is significantly attenuated in POMC neurons that receive a high density of AgRP puncta. These high-density AgRP inputs correlate with leptin levels in normal mice and are nearly absent in mice lacking leptin. The progression of increased AgRP innervation onto POMC somas is accelerated in hyperleptinemic, diet-induced obese mice. Together our study suggests that modulation of hypothalamic AgRP innervation constitutes one mechanism to counter the effects of the age-associated rise in leptin levels, thus sustaining body weight and fat mass at an elevated level in adulthood. (Endocrinology 154: 172-183, 2013)