Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice
Leptin receptor expression in hindbrain Glp-1 neurons regulates food intake and energy balance in mice
复制标题
DOI：
10.1172/jci43703
复制
发表时间：
2011-06-01
影响因子：
15.9
通讯作者：
Elmquist, Joel K.
中科院分区：
文献类型：
--
作者：
Scott, Michael M.;Williams, Kevin W.;Elmquist, Joel K.
瘦素是一种脂肪衍生的激素，它发出信号通知大脑营养状态；失去瘦素信号会导致明显的吞噬和肥胖。最近的工作已经确定了几组神经元参与了瘦素调节能量平衡的作用，但瘦素受体分布于大脑各处，而且瘦素信号在下丘脑以外的离散神经元群体中的功能尚未确定。在目前的研究中，我们建立了在配对的类同源盒2b(PHOX2B)启动子的控制下，使用Cre重组酶选择性地在后脑表达的长型瘦素受体(Lepr)的小鼠(PHOX2B Cre Lepr(FLOX/FLOX)小鼠)。在这些小鼠中，Lepr从驻留在孤束核中的高血糖素样1肽表达神经元中删除。与野生型对照组相比，PHOX2B Cre Lepr(FLOX/FLOX)小鼠吞噬功能增强，禁食后食物摄入量增加，体重增加速度更快。矛盾的是，PHOX2B Cre Lepr(FLOX/FLOX)小鼠也表现出代谢率增加，而不依赖于食物摄入量的运动活动的变化，并且葡萄糖稳态是正常的。总之，这些数据支持瘦素在后脑的直接作用在生理上的重要作用。
Leptin is an adipose-derived hormone that signals to inform the brain of nutrient status; loss of leptin signaling results in marked hyperphagia and obesity. Recent work has identified several groups of neurons that contribute to the effects of leptin to regulate energy balance, but leptin receptors are distributed throughout the brain, and the function of leptin signaling in discrete neuronal populations outside of the hypothalamus has not been defined. In the current study, we produced mice in which the long form of the leptin receptor (Lepr) was selectively ablated using Cre-recombinase selectively expressed in the hindbrain under control of the paired-like homeobox 2b (Phox2b) promoter (Phox2b Cre Lepr(flox/flox) mice). In these mice, Lepr was deleted from glucagon-like 1 peptide-expressing neurons resident in the nucleus of the solitary tract. Phox2b Cre Lepr(flox/flox) mice were hyperphagic, displayed increased food intake after fasting, and gained weight at a faster rate than wild-type controls. Paradoxically, Phox2b Cre Lepr(flox/flox) mice also exhibited an increased metabolic rate independent of a change in locomotor activity that was dependent on food intake, and glucose homeostasis was normal. Together, these data support a physiologically important role of direct leptin action in the hindbrain.