POMC Neuron BBSome Regulation of Body Weight is Independent of its Ciliary Function.
POMC Neuron BBSome Regulation of Body Weight is Independent of its Ciliary Function.
复制标题
DOI：
10.1093/function/zqad070
复制
发表时间：
2024
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
BBSome是Bardet-Biedl综合征（BBS）蛋白（包括BBS 1）的复合物，已成为能量稳态的关键调节因子。虽然BBSome最为人所知的是其通过涉及BBS 3的过程参与纤毛运输，但它也调节细胞膜受体的定位，这些受体是代谢调节的基础。在这里，我们表明，诱导型Bbs 1基因缺失选择性在proopiomelanocortin（POMC）神经元导致体重逐渐增加，这是与较高的脂肪量。相反，在POMC神经元中诱导性缺失Bbs 3基因不能影响体重和肥胖。有趣的是，POMC神经元中的BBS 1的缺失导致葡萄糖耐受不良和胰岛素不敏感，而这些神经元中的BBS 3缺乏与葡萄糖处理的轻微损伤相关，但与正常的胰岛素敏感性相关。BBS 1缺陷改变了5-HT 2C受体（5-HT 2CR）的质膜定位和神经肽Y 2受体（NPY 2 R）的纤毛运输，而BBS 3缺陷则破坏了BBSome的纤毛定位，但不影响5-HT 2CR的质膜表达，但减少了NPY 2 R向纤毛的运输。我们还表明，在BBS 1，而不是BBS 3的缺陷，改变线粒体动力学和减少总和磷酸化水平的动力蛋白样蛋白1（DRP 1）蛋白。重要的是，挽救DRP 1活性恢复了BBS 1缺陷细胞中的线粒体动力学和5-HT 2CR和NPY 2 R的定位。与BBS 3相比，BBS 1的缺失对POMC神经元诱发的能量和葡萄糖稳态的对比效应表明，BBSome对代谢的调节与这些神经元中的纤毛功能无关。
The BBSome, a complex of several Bardet-Biedl syndrome (BBS) proteins including BBS1, has emerged as a critical regulator of energy homeostasis. Although the BBSome is best known for its involvement in cilia trafficking, through a process that involve BBS3, it also regulates the localization of cell membrane receptors underlying metabolic regulation. Here, we show that inducible Bbs1 gene deletion selectively in proopiomelanocortin (POMC) neurons cause a gradual increase in body weight, which was associated with higher fat mass. In contrast, inducible deletion of Bbs3 gene in POMC neurons failed to affect body weight and adiposity. Interestingly, loss of BBS1 in POMC neurons led to glucose intolerance and insulin insensitivity, whereas BBS3 deficiency in these neurons is associated with slight impairment in glucose handling, but normal insulin sensitivity. BBS1 deficiency altered the plasma membrane localization of serotonin 5-HT2C receptor (5-HT2CR) and ciliary trafficking of neuropeptide Y2 receptor (NPY2R).In contrast, BBS3 deficiency, which disrupted the ciliary localization of the BBSome, did not interfere with plasma membrane expression of 5-HT2CR, but reduced the trafficking of NPY2R to cilia. We also show that deficiency in BBS1, but not BBS3, alters mitochondria dynamics and decreased total and phosphorylated levels of dynamin-like protein 1 (DRP1) protein. Importantly, rescuing DRP1 activity restored mitochondria dynamics and localization of 5-HT2CR and NPY2R in BBS1-deficient cells. The contrasting effects on energy and glucose homeostasis evoked by POMC neuron deletion of BBS1 versus BBS3 indicate that BBSome regulation of metabolism is not related to its ciliary function in these neurons.