Studies of cellular physiology and molecular endocrinology of orexin and MCH.

食欲素基因敲除小鼠表现出与人类发作性睡病患者惊人的相似的表型，食欲素基因敲除小鼠调节睡眠/觉醒状态，食欲素基因敲除小鼠是人类发作性睡病的模型，这种疾病的主要特征是快速眼动(REM)睡眠障碍。脑损伤的各种研究表明，下丘脑参与了摄食行为和能量平衡的调节。下丘脑多肽、食欲素/下克汀类位于下丘脑外侧的“摄食中心”。食欲素只在下丘脑的外侧合成，但它的神经纤维广泛分布在大脑各处。密集纤维投射见于中缝核、蓝斑、丘脑室旁核和弓状核。脑室注射食欲素刺激了食物的摄入，这表明神经肽在能量平衡中发挥了作用。食欲素纤维支配下丘脑室旁核、蓝斑和…弧更多的Uate核，这是摄食和体重调节的关键区域。下丘脑内侧和下丘脑外侧之间的联系可能连接外周代谢信号和皮质外套膜，从而在摄食和能量平衡的调节中发挥重要作用。我们研究了Ghrelin与存在于下丘脑外侧的两种促食欲素多肽--食欲素和黑色素浓缩激素(MCH)的解剖相互作用和功能关系。Ghrelin免疫反应的轴突终末与产生食欲素的神经元直接突触接触。侧脑室注射Ghrelin可诱导产生食欲素的神经元Fos表达，但不能诱导产生MCH的神经元表达Fos。Ghrelin在用抗NPY lgg预处理后仍能诱导食欲素产生神经元Fos的表达。预先给予抗食欲素-A和抗食欲素-B的LGG，但不使用抗MCH LGG，可减弱Ghrelin诱导的摄食。给予NPY受体拮抗剂进一步减弱Ghrelin对反食欲素-lggs处理的大鼠的摄食。在食欲素基因敲除的小鼠中，Ghrelin诱导的进食也受到抑制。这项研究确定了一条新的下丘脑通路，它将Ghrelin和增食欲素联系在一起，调节摄食行为和能量平衡。较少

Orexin knockout mice exhibit a phenotype strikingly similar to human narcolepsy patients, orexin regulates sleep/wakefulness states, and that orexin knockout mice are a model of human narcolepsy, a disorder characterized primarily by rapid eye movement (REM) sleep dysregulation.The hypothalamus has been implicated in the regulation of feeding behavior and energy homeostasis by various studies of brain lesion. The hypothalamic peptides, orexins/hypocretins were discovered in the lateral hypothalamus, "the feeding center". Orexins are synthesized only in the lateral hypothalamus, but its neuronal fibers are widely distributed throughout the brain. Dense fiber projections were seen in the raphe nucleus, locus coeruleus, paraventricular thalamic nucleus, and arcuate nucleus. Orexins injected intracerebroventricularly stimulated food intake, suggesting a role for the neuropeptide in energy homeostasis. Orexin fibers innervate the paraventricular hypothalamic nucleus, locus coeruleus and arc … More uate nucleus, area which are critical to feeding and body weight regulation. The connection between the medial hypothalamus and the lateral hypothalamus may link the peripheral metabolic signals with the cortical mantle and thereby play an important role in the regulation of feeding and energy homeostasis.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 lgG. Pretreatment with anti-orexin-A lgG and anti-orexin-B lgG, but not anti-MCH lgG, attenuated ghrelin-induced feeding. Administration of NPY receptor antagonist further attenuated ghrelin-induced feeding in rats treated with anti-orexin-lgGs. 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. Less