Pro-opiomelanocortin (POMC)-derived peptides and the regulation of energy homeostasis
Pro-opiomelanocortin (POMC)-derived peptides and the regulation of energy homeostasis
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DOI：
10.1016/j.mce.2008.09.007
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发表时间：
2009-03-05
影响因子：
4.1
通讯作者：
Tung, Y. C. Loraine
中科院分区：
文献类型：
--
作者：
Coll, Anthony P.;Tung, Y. C. Loraine
人类遗传数据表明，阿黑皮素原（POMC）合成或加工受损会导致肥胖。我们利用一种阿黑皮素原缺乏的小鼠模型（Pomc基因敲除）来探究POMC衍生肽在能量稳态中的作用。Pomc基因敲除小鼠的表型重现了先天性缺乏POMC的人类所出现的临床综合征。仅缺失一个Pomc基因拷贝就足以使小鼠易受高脂肪饮食的影响，这强调了一种导致肥胖的重要的基因 - 环境相互作用。我们的研究表明，POMC衍生肽对高脂肪饮食的反应有影响，包括对脂肪饮食偏好的重大影响。Pomc基因敲除小鼠的特殊之处在于，在没有循环糖皮质激素（GC）的情况下也会出现肥胖和多食。为了研究糖皮质激素与黑皮质素系统之间的相互作用，我们给Pomc基因敲除小鼠施用皮质酮。它们似乎对糖皮质激素的不良代谢影响高度敏感，会出现高血压，多食和肥胖加剧以及严重的胰岛素抵抗。对Pomc基因敲除小鼠进行糖皮质激素治疗会显著增加黑皮质素拮抗剂刺鼠相关蛋白（AgRP）的表达。正在对同时缺失AgRP和Pomc的小鼠进行的研究将确定这种糖皮质激素治疗所出现的代谢表型是由于缺乏黑皮质素肽、AgRP的未受拮抗作用还是两者兼而有之。（C）2008爱思唯尔爱尔兰有限公司。保留所有权利。
Human genetic data indicate impaired synthesis or processing of POMC results in obesity. We have used a mouse model of POMC deficiency (Pomc null) to explore the role of POMC-derived peptides in energy homeostasis. The phenotype of Pomc null mice recapitulates the clinical syndrome seen in humans congenitally lacking POMC. Loss of only one copy of the Pomc gene is sufficient to render mice susceptible to the effects of high fat feeding, emphasizing an important gene-environment interaction predisposing to obesity. Our studies indicate that POMC-derived peptides have influences on the response to a high fat diet, including a major influence on the dietary preference for fat. Pomc null mice are unusual in that obesity and hyperphagia develop in the absence of circulating glucocorticoid (GC). To investigate the interaction between GCs and the melanocortin system, we administered corticosterone to Pomc null mice. They appear hypersensitive to the adverse metabolic effects of GCs, developing hypertension, an exacerbation of both hyperphagia and obesity and a profound insulin resistance. GC treatment of Pomc null mice significantly increases the expression of the melanocortin antagonist agouti-related protein (AgRP). On-going studies in mice lacking both AgRP and Pomc will determine whether the metabolic phenotype seen with this GC therapy is due to a lack of melanocortin peptide, the unopposed action of AgRP or a combination of both. (C) 2008 Elsevier Ireland Ltd. All rights reserved.