Martin N M, Small C J, Sajedi A, Patterson M, Ghatei M A, Bloom S R
Department of Metabolic Medicine, Imperial College, Hammersmith Campus, London, UK.
Int J Obes Relat Metab Disord. 2004 Jul;28(7):886-93. doi: 10.1038/sj.ijo.0802646.
The role of the melanocortin system in the feeding effects of peripheral peptide YY(3-36) (PYY(3-36)) and ghrelin was investigated using the agouti (A(y)/a) mouse as a model of abnormal melanocortin signalling. Furthermore, we examined whether the ectopic expression of agouti protein in A(y)/a mice results in complete MC4-R inhibition, by studying the effects of peripheral alpha-melanocyte-stimulating hormone (alpha-MSH) and leptin on food intake.
Adult A(y)/a mice were studied in the pre-obese state (7-8 weeks) and obese state (14-15 weeks). Animals received PYY(3-36) (0.02 micromol/kg), NDP-alpha-MSH (0.2 micromol/kg), leptin (2 micromol/kg) (all 24 h fasted state) and ghrelin (0.2 micromol/kg) (fed state) by intraperitoneal (i.p.) injection. Age-matched A(y)/a controls received i.p. saline. A separate cohort of wild-type (WT), age-matched controls received the same peptide dose or saline. Food intake was measured at 1, 2, 4, 8 and 24 h post-injection and compared in all four groups. Plasma leptin-, ghrelin- and PYY-like immunoreactivity (IR) were measured using radioimmunoassay (RIA).
At 2 h post-injection, PYY(3-36) reduced food intake in pre-obese and obese A(y)/a mice, whereas ghrelin had no effect. Plasma ghrelin levels were significantly reduced in pre-obese and obese A(y)/a mice compared to WT controls. Peripheral administration of NDP-alpha-MSH and leptin acutely suppressed feeding (0-2 h) in pre-obese and obese A(y)/a mice.
Responsiveness of pre-obese and obese A(y)/a mice to PYY(3-36) suggests that the melanocortin system may not be essential for the anorectic effects of this peptide. Melanocortinergic antagonism by agouti protein in A(y)/a mice may be sufficient to block the effects of endogenous, but not exogenous PYY(3-36), alpha-MSH and leptin. The mechanism underlying ghrelin resistance in A(y)/a mice may result from antagonism of hypothalamic melanocortin receptors-4 by agouti protein, supporting a role for the melanocortin system in mediating ghrelin's actions.
以刺鼠（A(y)/a）小鼠作为黑皮质素信号异常的模型，研究黑皮质素系统在周围肽YY(3 - 36)（PYY(3 - 36)）和胃饥饿素的摄食效应中的作用。此外，我们通过研究外周α - 黑素细胞刺激素（α - MSH）和瘦素对食物摄入量的影响，来检验A(y)/a小鼠中刺鼠蛋白的异位表达是否导致黑皮质素 - 4受体（MC4 - R）完全抑制。
对处于肥胖前期（7 - 8周）和肥胖期（14 - 15周）的成年A(y)/a小鼠进行研究。动物通过腹腔注射接受PYY(3 - 36)（0.02微摩尔/千克）、NDP - α - MSH（0.2微摩尔/千克）、瘦素（2微摩尔/千克）（均处于禁食24小时状态）和胃饥饿素（0.2微摩尔/千克）（处于进食状态）。年龄匹配的A(y)/a对照小鼠接受腹腔注射生理盐水。另一组年龄匹配的野生型（WT）对照小鼠接受相同剂量的肽或生理盐水。在注射后1、2、4、8和24小时测量食物摄入量，并在所有四组中进行比较。使用放射免疫分析法（RIA）测量血浆瘦素、胃饥饿素和PYY样免疫反应性（IR）。
注射后2小时，PYY(3 - 36)减少了肥胖前期和肥胖期A(y)/a小鼠的食物摄入量，而胃饥饿素没有作用。与WT对照相比，肥胖前期和肥胖期A(y)/a小鼠的血浆胃饥饿素水平显著降低。外周给予NDP - α - MSH和瘦素可急性抑制肥胖前期和肥胖期A(y)/a小鼠的摄食（0 - 2小时）。
肥胖前期和肥胖期A(y)/a小鼠对PYY(3 - 36)有反应性，这表明黑皮质素系统可能不是该肽厌食作用所必需的。A(y)/a小鼠中刺鼠蛋白对黑皮质素能的拮抗作用可能足以阻断内源性但非外源性PYY(
