Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia
Distinct physiologic and neuronal responses to decreased leptin and mild hyperleptinemia
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DOI：
10.1210/en.140.11.4923
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发表时间：
1999-11-01
期刊：
影响因子：
4.8
通讯作者：
Flier, JS
中科院分区：
文献类型：
--
作者：
Ahima, RS;Kelly, J;Flier, JS
瘦素作用于下丘脑神经元的特定群体，以调节摄食行为、能量消耗和神经内分泌功能。然而，目前尚不清楚是否相同的神经回路在其完整的生物剂量反应曲线上介导瘦素作用，该曲线延伸范围很广，从饥饿期间观察到的低水平到肥胖症的高水平特征。在这里，我们发现，瘦素与禁食的特征下降导致神经肽Y（NPY）信使RNA（mRNA）的上升，以及POMC和可卡因和安非他明调节转录（CART）mRNA的下降。在禁食期间输注足以将血浆水平维持在生理范围内的瘦素防止了这些肽的表达的变化以及神经内分泌功能的变化，表明多个神经回路对瘦素在其低生理范围内的微小变化高度敏感。与此相反，血浆瘦素水平高于正常喂养范围的恒定皮下输注，产生显着减少的食物摄入量和体重，减少下丘脑弓状核中的NPY mRNA，但不影响mRNA的水平编码的促肾上腺皮质激素生成肽α-MSH，CART或CRH。这些结果表明，瘦素对下丘脑靶神经元在mRNA表达水平上的剂量反应特征是可变的，其中一些神经元（例如NPY）在宽剂量范围内响应，而其他神经元（例如POMC和CART）在低范围内显示有限的响应。这些结果进一步表明，介导从饥饿到进食状态的转变的瘦素的中心靶点可能不同于介导对过度喂养和肥胖的反应的靶点。
Leptin acts on specific populations of hypothalamic neurons to regulate feeding behavior, energy expenditure, and neuroendocrine function. It is not known, however, whether the same neural circuits mediate leptin action across its full biologic dose-response curve, which extends over a broad range, from low levels seen during starvation to high levels characteristic of obesity. Here, we show that the characteristic fall in leptin with fasting causes a rise in neuropeptide Y (NPY) messenger RNA (mRNA), as well as a fall in POMC and cocaine and amphetamine-regulated transcript (CART) mRNAs. Sc infusion of leptin sufficient to maintain plasma levels within the physiologic range during the fast prevents changes in the expression of these peptides, as well as changes in neuroendocrine function, demonstrating that multiple neural circuits are highly sensitive to small changes in leptin within its low physiologic range. In contrast, a modest elevation of plasma leptin above the normal fed range by constant sc infusion, which produced marked reduction in food intake and body weight, decreased NPY mRNA in the arcuate hypothalamic nucleus but did not affect the levels of mRNAs encoding the anorexigenic peptides alpha-MSH, CART or CRH. These results suggest that the dose response characteristics of leptin on hypothalamic target neurons at the level of mRNA expression are variable, with some neurons (e.g. NPY) responding across a broad dose range and others (e.g. POMC and CART) showing a limited response within the low range. These results further suggest that the central targets of leptin that mediate the transition from starvation to the fed state may be distinct from those that mediate the response to overfeeding and obesity.