Role of melanocortinergic neurons in feeding and the agouti obesity syndrome
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome
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DOI：
10.1038/385165a0
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发表时间：
1997-01-09
期刊：
影响因子：
64.8
通讯作者：
Cone, RD
中科院分区：
文献类型：
--
作者：
Fan, W;Boston, BA;Cone, RD
由于Agouti肽的异位表达，Agouti基因座的主要等位基因（A）在小鼠中引起肥胖综合征（1-6）。这种肽通常仅在皮肤中发现，是黑素细胞刺激的激素受体（MC1-R）的高亲和力拮抗剂（7），因此解释了Agouti对Eumelanin consantys的抑制作用，Agouti肽也是一种下丘脑黑色素素-4受体（MC4-R）的拮抗剂（7-9）。为了检验Agouti通过下丘脑黑色皮质素受体的拮抗作用引起肥胖的假说（7），我们确定了环状黑色皮质素类似物（10）是神经MC3的有效激动剂或拮抗剂（参考11，12）和MC4受体。激动剂MTII的脑室内给药抑制了四种模型中的喂养：禁食的C57BL/6J，OB/OB和A（Y）小鼠，以及被神经肽Y的小鼠。模仿SHU9119完全阻止了这种抑制作用。此外，SHU9119的给药可显着增强夜间喂养，或者受到先前的速度刺激的饲料。我们的数据表明，黑色皮质素能神经元对喂养行为施加了补品抑制。这种抑制信号的慢性破坏可能是Agouti肥胖综合征的解释。
DOMINANT alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide(1-6). This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R)(7), thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis, The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R)(7-9). To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors(7), we identified cyclic melanocortin analogues(10) that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and A(Y) mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome.