| Co-Investigator(Kenkyū-buntansha) |
IHARA Masaki Banyu Tsukuba Research Institute, Banyu Pharmaceutical Co., Ltd., Vice President, 創薬研究所, 副所長
HAYASHI Ujiro Suntory Institute for Medicinal Research & Development, Investigator, 医薬開発研究所, 主席研究院
ISHIDA Yasushi Department of Psychiatry, Professor, 医学部, 教授 (20212897)
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| Research Abstract |
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 ar
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cuate 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 further 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 studied. Less
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