Department of Neuroscience and Pharmacology, University of Iowa Carver College of Medicine, Iowa City, IA 52242, USA.
Veterans Affairs Health Care System, Iowa City, IA 52242, USA.
Function (Oxf). 2023 Dec 23;5(1):zqad070. doi: 10.1093/function/zqad070. eCollection 2024.
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 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 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-HTR) and ciliary trafficking of neuropeptide Y2 receptor (NPYR).In contrast, BBS3 deficiency, which disrupted the ciliary localization of the BBSome, did not interfere with plasma membrane expression of 5-HTR, but reduced the trafficking of NPYR 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-HTR and NPYR 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.
BBSome，一种由几个 Bardet-Biedl 综合征 (BBS) 蛋白组成的复合物，包括 BBS1，已成为能量平衡的关键调节剂。尽管 BBSome 最著名的是参与纤毛运输，通过涉及 BBS3 的过程，但它也调节代谢调节下的细胞膜受体的定位。在这里，我们表明，诱导性基因缺失选择性地在促肾上腺皮质激素释放激素（POMC）神经元中导致体重逐渐增加，这与更高的脂肪量有关。相比之下，在 POMC 神经元中诱导性缺失基因对体重和肥胖没有影响。有趣的是，BBS1 在 POMC 神经元中的缺失导致葡萄糖不耐受和胰岛素不敏感，而这些神经元中 BBS3 的缺乏与葡萄糖处理略有受损有关，但胰岛素敏感性正常。BBS1 缺失改变了血清素 5-HT2C 受体 (5-HTR) 的质膜定位和神经肽 Y2 受体 (NPYR) 的纤毛运输。相比之下，破坏 BBSome 纤毛定位的 BBS3 缺失不会干扰 5-HTR 的质膜表达，但会减少 NPYR 向纤毛的运输。我们还表明，BBS1 而不是 BBS3 的缺乏改变了线粒体动力学，并降低了动力蛋白样蛋白 1 (DRP1) 蛋白的总蛋白和磷酸化水平。重要的是，恢复 DRP1 活性恢复了 BBS1 缺陷细胞中 5-HTR 和 NPYR 的线粒体动力学和定位。POMC 神经元缺失 BBS1 而非 BBS3 对能量和葡萄糖稳态的影响表明，BBSome 对代谢的调节与其在这些神经元中的纤毛功能无关。
