INVOLVEMENT OF THE MELANOCORTIN SYSTEM IN REGUL OF LIPOLYSIS & BLOOD PRESSURE

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 该项目的目的是研究黑皮质素系统参与脂肪分解和血压的调节，并研究脂肪细胞中MCRs可能的替代信号通路。在分化为脂肪细胞的小鼠3 T3细胞系中进行的内部研究表明，MC 5受体和可能还有MC 2受体参与脂解的直接刺激（手稿在准备中），此外，初步数据表明，除cAMP外的其他信号传导途径参与黑皮质素介导的小鼠脂肪细胞脂解。下一步是检查小鼠原代脂肪细胞和脂肪组织，以更好地了解白色脂肪组织中MCR的分布和黑皮质素系统的生物学效应。由于已经描述了黑皮质素系统在脂解方面的显著物种差异（Boston & Cone 1996 a），因此研究其他物种（包括哺乳动物）脂肪组织中五种MCR的表达模式也很重要。人类），以鉴定在MC 4 R激动剂作为肥胖症药物的开发中研究这些作用的最佳物种。对于MC 4 R描述的一个可能的副作用是血压升高，并且正在遥测体内模型中研究黑皮质素系统对血压的影响，特别是MC 3和MC 4敲除小鼠。此外，还应确定在血压和脂解方面是否存在这些潜在的种属差异。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The aim of the project is to examine the involvement of the melanocortin system in the regulation of lipolysis and blood pressure and to characterise possible alternative signalling pathways of MCRs in adipocytes. In house studies in a mouse 3T3 cell line differentiated to adipocytes indicates that the MC5 receptor and possibly also the MC2 receptor are involved in direct stimulation of lipolysis (manuscript in preparation), and furthermore preliminary data indicates that other signalling pathways than cAMP are involved in the melanocortin mediated lipolysis of mouse adipocytes. Examination of mouse primary adipocytes and fat tissue is the next step in order to obtain a better understanding of the MCR distribution and the biological effects of the melanocortin system in white adipose tissue. As significant species differences with regard to lipolysis have been described for the melanocortin system (Boston & Cone 1996a), it is also important to characterise the expression pattern of the five MCR's in fat tissue from other species (incl. humans) in order to identify the species that is most optimal for studying these effects in the development of MC4R agonists as obesity drugs. A possible side effect described for the MC4R is increased blood pressure, and the effect of the melanocortin system on blood pressure are being investigated in telemeterised in vivo models, especially MC3 and MC4 knockout mice. Furthermore, it should be established whether these potential species differences exist with regard to blood pressure as well as lipolysis.