Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Division of Endocrinology and Metabolism, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX, USA ; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mol Metab. 2013 Oct 17;3(1):64-72. doi: 10.1016/j.molmet.2013.10.001. eCollection 2014 Feb.
The hormone ghrelin stimulates eating and helps maintain blood glucose upon caloric restriction. While previous studies have demonstrated that hypothalamic arcuate AgRP neurons are targets of ghrelin, the overall relevance of ghrelin signaling within intact AgRP neurons is unclear. Here, we tested the functional significance of ghrelin action on AgRP neurons using a new, tamoxifen-inducible AgRP-CreER(T2) transgenic mouse model that allows spatiotemporally-controlled re-expression of physiological levels of ghrelin receptors (GHSRs) specifically in AgRP neurons of adult GHSR-null mice that otherwise lack GHSR expression. AgRP neuron-selective GHSR re-expression partially restored the orexigenic response to administered ghrelin and fully restored the lowered blood glucose levels observed upon caloric restriction. The normalizing glucoregulatory effect of AgRP neuron-selective GHSR expression was linked to glucagon rises and hepatic gluconeogenesis induction. Thus, our data indicate that GHSR-containing AgRP neurons are not solely responsible for ghrelin's orexigenic effects but are sufficient to mediate ghrelin's effects on glycemia.
激素 ghrelin 可刺激摄食，并有助于在热量限制时维持血糖。虽然之前的研究已经证明下丘脑弓状核 AgRP 神经元是 ghrelin 的靶点，但 ghrelin 信号在完整的 AgRP 神经元中的整体相关性尚不清楚。在这里，我们使用一种新的、他莫昔芬诱导型 AgRP-CreER(T2)转基因小鼠模型，测试了 ghrelin 对 AgRP 神经元作用的功能意义，该模型允许在成年 GHSR 缺失小鼠的 AgRP 神经元中时空特异性地重新表达生理水平的 ghrelin 受体 (GHSRs)，而这些小鼠原本缺乏 GHSR 表达。AgRP 神经元选择性 GHSR 再表达部分恢复了给予 ghrelin 的摄食反应，并完全恢复了热量限制时观察到的血糖降低。AgRP 神经元选择性 GHSR 表达的正常血糖调节作用与胰高血糖素升高和肝糖异生诱导有关。因此，我们的数据表明，含有 GHSR 的 AgRP 神经元不仅负责 ghrelin 的摄食作用，而且足以介导 ghrelin 对血糖的作用。
