Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway
Syndecan-3 modulates food intake by interacting with the melanocortin/AgRP pathway
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DOI：
10.1111/j.1749-6632.2003.tb03163.x
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
Seeley, RJ
中科院分区：
文献类型：
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作者：
Reizes, O;Benoit, SC;Seeley, RJ
Syndecan-3 在发育中的神经系统和成人大脑中表达，通过与中枢神经系统黑皮质素系统的相互作用来改变进食行为，该系统对食物摄入和身体脂肪储存提供关键的滋补抑制。多种体外和转基因数据支持这样的假设：syndecan-3 通过 syndecan-3 促进刺鼠相关蛋白 (AgRP) 调节黑皮质素活性，AgRP 是黑皮质素-3 和 -4 受体上 α-黑素细胞刺激激素 (α-MSH) 的竞争性拮抗剂。与这一假设一致，缺乏 Syndecan-3 的小鼠（因此预计 AgRP 的效果较差）对黑皮质素激动剂 MTII 抑制食物摄入的作用更敏感。此外，我们利用了 Syndecan-3 对 AgRP 的促进作用仅限于与细胞膜结合时的事实。对从细胞膜上裂解 syndecan-3 的酶进行药理学抑制会导致禁食大鼠的食物摄入量增加，从而导致 AgRP 水平升高。此外，脱落过程似乎在生理条件下受到调节，因为脱落过程的假定抑制剂，即金属蛋白酶-3（TIMP-3）组织抑制剂，会因食物匮乏而增加。这些观察结果有助于推测 Syndecan-3 对黑皮质素信号传导的调节有助于能量平衡的正常控制。总的来说，数据表明 Syndecan-3 对黑皮质素对能量平衡的调节是通过 TIMP-3 敏感金属蛋白酶的作用来调节的。
Syndecan-3, expressed in the developing nervous system and adult brain, alters feeding behavior through its interaction with the CNS melanocortin system, which provides critical tonic inhibition of both food intake and body adipose stores. A variety of both in vitro and transgenic data supports the hypothesis that syndecan-3 modulates melanocortin activity via syndecan-3 facilitation of agouti-related protein (AgRP), a competitive antagonist of alpha-melanocyte-stimulating hormone (alpha-MSH) at the melanocortin-3 and -4 receptors. Consistent with this hypothesis, mice lacking syndecan-3, which therefore would be predicted to have less effective AgRP, are more sensitive to inhibition of food intake by the melanocortin agonist MTII. Additionally, we took advantage of the fact that syndecan-3 facilitation of AgRP is limited to when it is bound to the cell membrane. Pharmacologic inhibition of the enzyme that cleaves syndecan-3 from the cell membrane leads to increased food intake in fasted rats, which have elevated levels of AgRP. Furthermore, the shedding process appears to be regulated under physiologic conditions, because a putative inhibitor of the shedding process, tissue inhibitor of metalloprotease-3 (TIMP-3), is increased by food deprivation. These observations contribute to the hypothesis that syndecan-3 regulation of melanocortin signaling contributes to the normal control of energy balance. Collectively, the data suggest that the modulation of melanocortin regulation of energy balance by syndecan-3 is modulated by the action of a TIMP-3-sensitive metalloprotease.