NPY antagonism reduces adiposity and attenuates age-related imbalance of adipose tissue metabolism
NPY antagonism reduces adiposity and attenuates age-related imbalance of adipose tissue metabolism
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DOI：
10.1096/fj.14-258384
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发表时间：
2014-12-01
期刊：
影响因子：
4.8
通讯作者：
Shimokawa, Isao
中科院分区：
文献类型：
--
作者：
Park, Seongjoon;Fujishita, Chika;Shimokawa, Isao
神经肽Y（neuropeptide Y，NPY）是一种促食欲激素，不仅参与下丘脑对食欲的调节，还参与脂代谢的外周调节。然而，由NPY触发的调节脂质代谢的细胞内机制知之甚少。在这里，我们报告说，神经肽Y缺乏减少白色脂肪组织（WAT）的质量和改善与年龄相关的脂肪组织代谢失衡的小鼠。发现参与脂肪生成/脂肪生成的基因表达减少，而参与脂解的蛋白质在NPY敲除小鼠的性腺WAT（gWAT）中增加。这些变化与激活的SIRT 1和PPAR γ介导的通路有关。此外，与年龄相关的从头脂肪生成的gWAT和腹股沟WAT的产热减少被抑制NPY缺乏。使用3 T3-L1细胞的进一步分析表明，NPY通过Y1受体抑制脂解，并在cAMP反应元件结合蛋白（CREB）和SIRT 1蛋白表达减少后增强脂肪生成。因此，NPY似乎通过CREB-SIRT 1信号通路作为脂肪组织代谢的关键调节剂。总之，NPY缺乏可减少肥胖并改善与年龄相关的脂肪组织代谢失衡，这表明NPY的拮抗作用可能是药物开发的一个有希望的靶点，以预防与年龄相关的代谢疾病。
An orexigenic hormone, neuropeptide Y (NPY), plays a role not only in the hypothalamic regulation of appetite, but also in the peripheral regulation of lipid metabolism. However, the intracellular mechanisms triggered by NPY to regulate lipid metabolism are poorly understood. Here we report that NPY deficiency reduces white adipose tissue (WAT) mass and ameliorates the age-related imbalance of adipose tissue metabolism in mice. Gene expression involved in adipogenesis/lipogenesis was found to decrease, whereas proteins involved in lipolysis increased in gonadal WAT (gWAT) of NPY-knockout mice. These changes were associated with an activated SIRT1- and PPAR gamma-mediated pathway. Moreover, the age-related decrease of de novo lipogenesis in gWAT and thermogenesis in inguinal WAT was inhibited by NPY deficiency. Further analysis using 3T3-L1 cells showed that NPY inhibited lipolysis through the Y1 receptor and enhanced lipogenesis following a reduction in cAMP response element-binding protein (CREB) and SIRT1 protein expression. Therefore, NPY appears to act as a key regulator of adipose tissue metabolism via the CREB-SIRT1 signaling pathway. Taken together, NPY deficiency reduces adiposity and ameliorates the age-related imbalance of adipose tissue metabolism, suggesting that antagonism of NPY may be a promising target for drug development to prevent age-related metabolic diseases.