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

食欲素和 MCH 的细胞生理学和分子内分泌学研究。

• 批准号: 12470222
• 负责人: YAMAGUCHI Hideki
• 金额: $ 9.02万
• 依托单位: Miyazaki Medical College
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2002
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-12470222/
• 关键词: orexin; MCH; lateral hypothalamus; gene expression; feeding regulation; immunohistochemistry; knockout mice; in situ hybridization; 摂食調製; 脳幹モノアミン系; ノックアウトマウス、

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

食欲素基因敲除小鼠表现出与人类发作性睡病患者惊人相似的表型，食欲素调节睡眠/觉醒状态，食欲素基因敲除小鼠是人类发作性睡病的模型，人类发作性睡病是一种主要以快速眼动（REM）睡眠失调为特征的疾病。下丘脑肽，食欲素/下丘脑泌素被发现在外侧下丘脑，“进食中心”。食欲素仅在外侧下丘脑合成，但其神经元纤维广泛分布于整个大脑。在中缝核、蓝斑、丘脑室旁核和弓状核可见密集的纤维投射。脑室内注射食欲素刺激食物摄入，表明神经肽在能量稳态中的作用。食欲素纤维支配下丘脑室旁核、蓝斑和弧 ...更多信息 尾状核，对摄食和体重调节至关重要的区域。内侧下丘脑和外侧下丘脑之间的联系可能将外周代谢信号与皮质外套联系起来，从而在摄食和能量稳态的调节中发挥重要作用。Ghrelin免疫反应阳性的轴突终末与产生食欲素的神经元直接突触接触。脑室内给药的ghrelin诱导Fos的表达，神经元激活的标志物，在食欲素产生的神经元，但不是在MCH产生的神经元。Ghrelin在用抗NPY IgG预处理后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，而不是抗MCH IgG，减弱ghrelin诱导的摄食。施用NPY受体拮抗剂进一步减弱用抗食欲素-IgG处理的大鼠中生长素释放肽诱导的进食。Ghrelin诱导的进食在食欲素敲除小鼠中也被抑制。这项研究确定了一个新的下丘脑通路，连接生长激素释放肽和食欲素在调节摄食行为和能量稳态。少

项目成果

Tanaka M, Naruo T, Nagai N, Kuroki N, Shiiya T, Nakazato M, Matsukura S, Nozoe S: "Habitual binge/purge behavior influences circulating ghrelin levels in eating disorders."J Psychiatr Res. 37. 17-22 (2002)

Tanaka M、Naruo T、Nagai N、Kuroki N、Shiiya T、Nakazato M、Matsukura S、Nozoe S：“习惯性暴饮暴食/清除行为影响饮食失调中的循环胃饥饿素水平。”J Psychiatr Res。

Toshinai K, Date Y, Murakami N, Shimada M, Guan J, Wang Q, Funahashi H, Sakurai T, Shioda S, Matsukura S, Kangawa K, Nakazato: "Ghrelin-induced food intake is mediated via the orexin pathway"Endocrinology. 144. 1506-1512 (2003)

Toshinai K、Date Y、Murakami N、Shimada M、Guan J、Wang Q、Funahashi H、Sakurai T、Shioda S、Matsukura S、Kangawa K、Nakazato：“Ghrelin 诱导的食物摄入是通过食欲素途径介导的”内分泌学。

Date Y, Nakazato M, Murakami N, Kojima M, Kangawa K, Matsukura S: "Ghrelin acts in the central nervous system to stimulate gastric acid secretion"Biochem Biophys Res Commun,. 208. 904-907 (2001)

Date Y、Nakazato M、Murakami N、Kojima M、Kangawa K、Matsukura S：“Ghrelin 在中枢神经系统中发挥作用，刺激胃酸分泌”Biochem Biophys Res Commun，。

Nondal MS, Nakazato M, Matsukara S.: "Characrerization of orexins(hypocretins)and melanin concentrating hormone in the genetically obese mice"Regul Pept,. 104. 21-25 (2002)

Nondal MS、Nakazato M、Matsukara S.：“遗传性肥胖小鼠中食欲素（下丘脑分泌素）和黑色素浓缩激素的表征”Regul Pept，。

Shiiya T, Nakazato M, Mizuta M, Date Y, Mondal MS, Tanaka M, Nozoe S, Hosoda H, Kangawa K, Matsukura S: "Plasma ghrelin levels in lean and obese humans and the effect of glucose on ghrelin secretion"J Clin Endocrinol Metab,. 87. 240-244 (2002)

Shiiya T、Nakazato M、Mizuta M、Date Y、Mondal MS、Tanaka M、Nozoe S、Hosoda H、Kangawa K、Matsukura S：“瘦人和肥胖人群的血浆生长素释放肽水平以及葡萄糖对生长素释放肽分泌的影响”J Clin