Nijenhuis W A, Oosterom J, Adan R A
Molecular Neuroscience Rudolf Magnus Institute for Neurosciences University Medical Center Utrecht Utrecht, the Netherlands 3584 CG.
Mol Endocrinol. 2001 Jan;15(1):164-71. doi: 10.1210/mend.15.1.0578.
The central melanocortin (MC) system has been demonstrated to act downstream of leptin in the regulation of body weight. The system comprises alpha-MSH, which acts as agonist, and agouti-related protein (AgRP), which acts as antagonist at the MC3 and MC4 receptors (MC3R and MC4R). This property suggests that MCR activity is tightly regulated and that opposing signals are integrated at the receptor level. We here propose another level of regulation within the melanocortin system by showing that the human (h) MC4R displays constitutive activity in vitro as assayed by adenylyl cyclase (AC) activity. Furthermore, human AgRP(83-132) acts as an inverse agonist for the hMC4R since it was able to suppress constitutive activity of the hMC4R both in intact B16/G4F melanoma cells and membrane preparations. The effect of AgRP(83-132) on the hMC4R was blocked by the MC4R ligand SHU9119. Also the hMC3R and the mouse(m)MC5R were shown to be constitutively active. AgRP(83-132) acted as an inverse agonist on the hMC3R but not on the mMC5R. Thus, AgRP is able to regulate MCR activity independently of alpha-MSH. These findings form a basis to further investigate the relevance of constitutive activity of the MC4R and of inverse agonism of AgRP for the regulation of body weight.
中枢黑皮质素（MC）系统已被证明在体重调节中作用于瘦素下游。该系统包括作为激动剂的α-促黑素（α-MSH）和作为MC3和MC4受体（MC3R和MC4R）拮抗剂的刺鼠相关蛋白（AgRP）。这一特性表明MCR活性受到严格调控，且相反的信号在受体水平整合。我们在此通过显示人（h）MC4R在体外经腺苷酸环化酶（AC）活性测定具有组成性活性，提出黑皮质素系统内的另一层调节。此外，人AgRP(83 - 132)作为hMC4R的反向激动剂，因为它能够在完整的B16/G4F黑色素瘤细胞和膜制剂中抑制hMC4R的组成性活性。AgRP(83 - 132)对hMC4R的作用被MC4R配体SHU9119阻断。同样，hMC3R和小鼠（m）MC5R也显示具有组成性活性。AgRP(83 - 132)对hMC3R起反向激动剂作用，但对mMC5R不起作用。因此，AgRP能够独立于α-MSH调节MCR活性。这些发现为进一步研究MC4R的组成性活性和AgRP的反向激动作用与体重调节的相关性奠定了基础。
