Nijenhuis Wouter A J, Garner Keith M, van Rozen Rea J, Adan Roger A H
Rudolf Magnus Institute of Neuroscience, Department of Pharmacology and Anatomy, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.
J Biol Chem. 2003 Jun 20;278(25):22939-45. doi: 10.1074/jbc.M211326200. Epub 2003 Apr 9.
The melanocortin-4 receptor (MC4R) plays an important role in the regulation of body weight in rodents. Mutations in the coding region of the MC4R are found more frequently in obese individuals, supporting the hypothesis that also in humans deficient melanocortin signaling may lead to obesity. Family studies that were carried out to demonstrate the relevance of single mutations for obesity were mostly inconclusive, most likely due to small sample size and complexity of the trait. In addition, the existing pharmacological data of the mutant receptors are limited in that for most mutations the effect on receptor expression level and Agouti-related protein (AgRP) pharmacology have not been studied. The aim of the present study was to gain further insight into the impact of the MC4R mutations on receptor function. Eleven missense mutations were tested for cell surface expression, affinity for alpha-melanocyte-stimulating hormone (alpha-MSH) and AgRP-(83-132), and the biological response to alpha-MSH. All mutants were poorly expressed at the cell surface, as measured by 125I-[Nle4-D-Phe7]alpha-MSH binding, and only a few mutants showed altered pharmacology for alpha-MSH and AgRP. Hemagglutinin-tagged mutant receptors were retained in the intracellular environment. These pharmacological data provide a basis to estimate the quantitative effect of MC4R mutations for the development of obesity.
黑皮质素-4受体（MC4R）在调节啮齿动物体重方面发挥着重要作用。在肥胖个体中，MC4R编码区的突变更为常见，这支持了一种假说，即在人类中，黑皮质素信号传导缺陷也可能导致肥胖。为证明单个突变与肥胖的相关性而开展的家族研究大多没有定论，这很可能是由于样本量小以及该性状的复杂性所致。此外，现有突变受体的药理学数据有限，因为对于大多数突变而言，其对受体表达水平和刺鼠相关蛋白（AgRP）药理学的影响尚未得到研究。本研究的目的是进一步深入了解MC4R突变对受体功能的影响。对11个错义突变进行了细胞表面表达、对α-黑素细胞刺激素（α-MSH）和AgRP-（83-132）的亲和力以及对α-MSH的生物学反应测试。通过125I-[Nle4-D-Phe7]α-MSH结合测定，所有突变体在细胞表面的表达均较差，并且只有少数突变体对α-MSH和AgRP的药理学表现出改变。带有血凝素标签的突变受体保留在细胞内环境中。这些药理学数据为评估MC4R突变对肥胖发生发展的定量影响提供了依据。
