Toshinai Koji, Date Yukari, Murakami Noboru, Shimada Mitsushi, Mondal Muhtashan S, Shimbara Takuya, Guan Jian-Lian, Wang Qing-Ping, Funahashi Hisayuki, Sakurai Takeshi, Shioda Seiji, Matsukura Shigeru, Kangawa Kenji, Nakazato Masamitsu
Department of Internal Medicine, Miyazaki Medical College, Miyazaki 889-1692, Japan.
Endocrinology. 2003 Apr;144(4):1506-12. doi: 10.1210/en.2002-220788.
The hypothalamus regulates energy intake by integrating the degree of starvation or satiation with the status of the environment through a variety of neuronal and blood-derived signals. Ghrelin, a peptide produced in the stomach and hypothalamus, stimulates feeding and GH secretion. Centrally administered ghrelin exerts an orexigenic activity through the neuropeptide Y (NPY) and agouti-related protein systems. The interaction between ghrelin and other hypothalamic orexigenic peptides, however, has not been clarified. Here, we investigated the anatomical interactions and functional relationship between ghrelin and two orexigenic peptides, orexin and melanin-concentrating hormone (MCH), present in the lateral hypothalamus. Ghrelin-immunoreactive axonal terminals made direct synaptic contacts with orexin-producing neurons. Intracerebroventricular administration of ghrelin induced Fos expression, a marker of neuronal activation, in orexin-producing neurons but not in MCH-producing neurons. Ghrelin remained competent to induce Fos expression in orexin-producing neurons following pretreatment with anti-NPY IgG. Pretreatment with anti-orexin-A IgG and anti-orexin-B IgG, but not anti-MCH IgG, attenuated ghrelin-induced feeding. Administration of NPY receptor antagonist further attenuated ghrelin-induced feeding in rats treated with anti-orexin-IgGs. Ghrelin-induced feeding was also suppressed in orexin knockout mice. This study identifies a novel hypothalamic pathway that links ghrelin and orexin in the regulation of feeding behavior and energy homeostasis.
下丘脑通过多种神经和血液衍生信号，将饥饿或饱腹感的程度与环境状态整合起来，从而调节能量摄入。胃饥饿素是一种在胃和下丘脑中产生的肽，可刺激进食和生长激素分泌。中枢给予胃饥饿素通过神经肽Y（NPY）和刺鼠相关蛋白系统发挥促食欲活性。然而，胃饥饿素与其他下丘脑促食欲肽之间的相互作用尚未阐明。在此，我们研究了胃饥饿素与存在于下丘脑外侧的两种促食欲肽——食欲素和促黑素细胞激素（MCH）之间的解剖学相互作用和功能关系。胃饥饿素免疫反应性轴突终末与产生食欲素的神经元形成直接突触联系。脑室内注射胃饥饿素可诱导产生食欲素的神经元中Fos表达（神经元激活的标志物），但在产生MCH的神经元中未诱导。在用抗NPY IgG预处理后，胃饥饿素仍能诱导产生食欲素的神经元中Fos表达。用抗食欲素-A IgG和抗食欲素-B IgG预处理可减弱胃饥饿素诱导的进食，但抗MCH IgG预处理则不能。给予NPY受体拮抗剂可进一步减弱用抗食欲素IgG处理的大鼠中胃饥饿素诱导的进食。在食欲素基因敲除小鼠中，胃饥饿素诱导的进食也受到抑制。本研究确定了一条在下丘脑新的通路，该通路在进食行为和能量稳态调节中连接胃饥饿素和食欲素。
