Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the Agouti obesity syndrome
Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the Agouti obesity syndrome
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DOI：
10.1210/me.11.5.630
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发表时间：
1997-05-01
影响因子：
--
通讯作者：
Cone, RD
中科院分区：
文献类型：
--
作者：
Kesterson, RA;Huszar, D;Cone, RD
在agglutinase基因座的显性突变诱导小鼠的几种表型变化，包括黄色色素沉着（黑色素沉着）的外套和成年发病肥胖。非色素表型的变化与agouti基因座是由于异位表达的agouti信号蛋白（ASP），和pheomelanizing影响毛色是由于ASP拮抗α-MSH结合黑素细胞MC 1受体。最近已经证明，下丘脑黑皮质素受体的药理学拮抗作用或黑皮质素4受体（MC 4-R）的遗传缺失概括了缺乏性肥胖综合征的各个方面，从而确定中枢黑皮质素能信号传导的慢性中断是刺豚鼠诱导的肥胖的原因。为了了解更多关于这些黑素皮质素能肥胖综合征的潜在下游效应物，我们研究了食欲肽甘丙肽和神经肽Y（NPY）的表达，以及致死黄（AY），MC 4-R敲除（MC 4-RKO）和瘦素缺陷（ob/ob）小鼠中的食欲POMC。在任何肥胖模型中均未观察到甘丙肽或POMC基因表达的显著变化。用反义神经肽Y探针进行的原位杂交显示，肥胖AY小鼠弓状核神经肽Y mRNA水平与同窝出生的C57 BL/6 J小鼠相当。然而，在一个新的网站，下丘脑背内侧核（DMH）的神经肽Y的高水平表达。在肥胖的MC 4-RKO纯合（-/-）小鼠中也观察到DMH中NPY的表达，但在瘦的杂合（+）或野生型（+/+）对照小鼠中未观察到。这表明DMH是一个脑区，其功能因黑皮质素能信号传导的中断而改变，并表明该核可能通过升高NPY表达而在黑皮质素能肥胖综合征中起病因作用。
Dominant mutations at the agouti locus induce several phenotypic changes in the mouse including yellow pigmentation (phaeomelanization) of the coat and adult-onset obesity. Nonpigmentary phenotypic changes associated with the agouti locus are due to ectopic expression of the agouti-signaling protein (ASP), and the pheomelanizing effects on coat color are due to ASP antagonism of alpha-MSH binding to the melanocyte MC1 receptor. Recently it has been demonstrated that pharmacological antagonism of hypothalamic melanocortin receptors or genetic deletion of the melanocortin 4 receptor (MC4-R) recapitulates aspects of the agouti obesity syndrome, thus establishing that chronic disruption of central melanocortinergic signaling is the cause of agouti-induced obesity. To learn more about potential downstream effecters involved in these melanocortinergic obesity syndromes, we have examined expression of the orexigenic peptides galanin and neuropeptide Y (NPY), as well as the anorexigenic POMC in lethal yellow (AY), MC4-R knockout (MC4-RKO), and leptin-deficient (ob/ob) mice. No significant changes in galanin or POMC gene expression were seen in any of the obese models. In situ hybridizations using an antisense NPY probe demonstrated that in obese AY mice, arcuate nucleus NPY mRNA levels were equivalent to that of their C57BL/6J littermates. However, NPY was expressed at high levels in a new site, the dorsal medial hypothalamic nucleus (DMH). Expression of NPY in the DMH was also seen in obese MC4-RKO homozygous (-/-) mice, but not in lean heterozygous (+) or wild type (+/+) control mice. This identifies the DMH as a brain region that is functionally altered by the disruption of melanocortinergic signaling and suggests that this nucleus, possibly via elevated NPY expression, may have an etiological role in the melanocortinergic obesity syndrome.