Melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity
Melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity
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DOI：
10.1021/jm058239j
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发表时间：
2006-07-13
影响因子：
7.3
通讯作者：
Zhou, Huiqiang
中科院分区：
文献类型：
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作者：
Handlon, Anthony L.;Zhou, Huiqiang
肥胖是一系列危险因素的组成部分，称为代谢综合征，其特征是高血压、胰岛素抵抗、血脂异常和内脏过度肥胖。脂肪组织不仅仅是甘油三酯的被动储存库。它也是产生和分泌瘦素的内分泌腺，瘦素是连接外周肥胖与摄食和能量消耗的中央控制的反馈回路中的关键介质。 1, 2 随着脂肪增加，会产生更多瘦素。正常生理条件下，瘦素进入下丘脑，抑制神经肽Y（NPY）、黑色素浓缩激素（MCH）、食欲素、甘丙肽和刺鼠相关蛋白（AGRP）等促食欲神经肽的形成。下丘脑瘦素同时上调食欲肽，例如 R 黑素细胞刺激激素 (R-MSH)、促肾上腺皮质激素释放激素 (CRH) 以及可卡因和安非他明调节转录物 (CART)。 3 肥胖的特点是对瘦素产生抵抗，其原因已成为许多研究的主题，但可能是由于大脑中瘦素受体信号传导的故障所致。 4 肥胖患者的循环瘦素水平较高，而重组瘦素作为抗肥胖治疗的结果好坏参半。 5 相反，药物干预可以针对在瘦素信号传导下游起作用的促食欲和厌食神经肽受体。黑色素浓缩激素 1 受体 (MCHR-1) 是一种促食欲神经肽受体，已成为治疗肥胖症的令人兴奋的药物靶标。在本文中，我们打算概述支持 MCH 拮抗剂在肥胖治疗中发挥作用的基本原理，并回顾迄今为止在发现 MCHR-1 拮抗剂方面所取得的进展。我们还将讨论 MCH 拮抗剂在肥胖治疗中可能存在的一些局限性。对于 MCH 领域的其他观点，我们引导读者阅读最近出现的几篇精彩评论。 6-10 MCH 于 1983 年首次从鲑鱼垂体中分离出来，它在鱼鳞色素沉着中发挥作用。 MCH 是一种由 19 个氨基酸组成的环肽，具有单个二硫桥，在迄今为止研究的所有哺乳动物中都是相同的。 7 1999 年，两个研究小组同时报道，MCH 结合并激活以前的孤儿受体 SLC-1（生长抑素样受体，也称为 GPR24）。 11, 12 新鉴定的 MCH-1 受体 (MCHR-1) 是 7TM GPCR（七跨膜 G 蛋白偶联受体）受体超家族的成员。 2001 年，第二个人类 MCH 受体 (MCHR-2) 被鉴定出来，它与 MCHR-1 具有 38% 的氨基酸同一性。 13 MCHR-2 在啮齿动物中不表达，并且缺乏动物模型阻碍了研究 MCHR-2 在喂养和能量平衡中的作用的努力。
Obesity is one component of a collection of risk factors, termed metabolic syndrome, that is characterized by high blood pressure, insulin resistance, dyslipidemia, and excessive visceral adiposity. Adipose tissue is more than a passive repository of triglycerides. It is also an endocrine gland that produces and excretes the hormone leptin, which serves as a key mediator in the feedback loop linking peripheral adiposity with the central control of feeding and energy expenditure. 1, 2 As fatness increases, more leptin is produced. Under normal physiological conditions, leptin enters the hypothalamus and inhibits the formation of orexigenic neuropeptides such as neuropeptide Y (NPY), melanin-concentrating hormone (MCH), orexin, galanin, and agouti-related protein (AGRP). Hypothalamic leptin simultaneously up-regulates anorectic peptides such as R-melanocyte stimulating hormone (R-MSH), corticotropin-releasing hormone (CRH), and cocaine-and amphetamine-regulated transcript (CART). 3 Obesity is characterized by resistance to leptin, the cause of which has been the subject of much investigation, but may result from a failure of leptin receptor signaling in the brain. 4 Obese patients are found to have high levels of circulating leptin, and administering recombinant leptin as an antiobesity treatment has given mixed results. 5 Instead, pharmaceutical intervention could be directed toward the orexigenic and anorectic neuropeptide receptors that operate downstream of leptin signaling.One of the orexigenic neuropeptide receptors that has emerged as an exciting drug target for the treatment of obesity is melaninconcentrating hormone-1 receptor (MCHR-1). In this article we intend to outline the rationale supporting a role for MCH antagonists in the treatment of obesity and to review the progress that has been made to date in the discovery of MCHR-1 antagonists. We will also discuss some of the possible limitations that MCH antagonists may have in the treatment of obesity. For other perspectives in the MCH field, we direct the reader to several excellent reviews that have appeared recently. 6-10 MCH was first isolated in 1983 from salmon pituitaries, where it has a role in pigmentation of fish scales. MCH is a cyclic peptide of 19 amino acids with a single disulfide bridge that is identical in all mammals studied so far. 7 In 1999 two research groups reported simultaneously that MCH binds to and activates the formerly orphan receptor SLC-1 (somatostatin-like receptor, also known as GPR24). 11, 12 The newly identified MCH-1 receptor (MCHR-1) is a member of the 7TM GPCR (seven transmembrane G-protein-coupled receptor) superfamily of receptors. In 2001 a second human MCH receptor was identified (MCHR-2) that shares 38% amino acid identity with MCHR-1. 13 MCHR-2 is not expressed in rodents, and the lack of animal models has hampered efforts to investigate the role of MCHR-2 in feeding and energy balance.