Lztfl1/BBS17 controls energy homeostasis by regulating the leptin signaling in the hypothalamic neurons

在前脑的视下丘表明小径的 Leptin 受体(LepRb ) 响应一个改变的精力状态控制食物吸入和精力开销。在表明小径的 LepRb 的缺点能导致 leptin 抵抗和肥胖。象 1 一样的白氨酸拉链抄写因素(Lztfl1 )/BBS17 是 Bardet-Biedl 症候群(BBS ) 的一个成员基因家庭。人的 BBS 病人包括肥胖有大量病理。位于调整 Lztfl1 的肥胖下面的细胞、分子的机制是未知的。这里，我们产生了 Lztfl1 Lztfl1 能全球性并且以织物特定的方式在被删除的 f/f 老鼠模型。全球 Lztfl1 缺乏包括肥胖导致了多种的显型。Lztfl1 / 老鼠是 hyperphagic 并且作为 WT 同窝出生的人显示出类似的精力开销。Lztfl1 / 老鼠的肥胖的显型被 Lztfl1 的损失在大脑然而并非在 adipocytes 引起。Lztfl1 / 老鼠是 leptin 抵抗的。Lztfl1 的 Inactivation 在在 leptin 刺激之上在视下丘表明小径的 LepRb 废除了 Stat3 的 phosphorylation。Lztfl1 的删除没在 LepRb 膜本地化上有效果。而且，我们观察了胚胎的成纤维细胞(MEF ) 有的那只 Lztfl1 / 老鼠显著地更长的睫比 WT MEF。我们识别了潜在地与 Lztfl1 交往的几蛋白质。当这些蛋白质被知道涉及肌动朊 / 细胞骨架动力学的规定，我们建议 Lztfl1 可以调整 leptin 经由这些蛋白质发信号和睫的结构。我们的学习在在控制精力动态平衡的视下丘表明小径的 LepRb 作为一个新奇播放器识别了 Lztfl1。

Leptin receptor （LepRb） signaling pathway in the hypothalamus of the forebrain controls food intake and energy expenditure in response to an altered energy state. Defects in the LepRb signaling pathway can result in leptin-resistance and obesity. Leucine zipper transcription factor like 1 （Lztfl1）/BBS17 is a member of the Bardet-Biedl syndrome （BBS） gene family. Human BBS patients have a wide range of pathologies including obesity. The cellular and molecular mechanisms underlying Lztfl1-regulated obesity are unknown. Here, we generated Lztfl1lf/f mouse model in which Lztfl1 can be deleted globally and in tissue-specific manner. Global Lztfl1 deficiency resulted in pleiotropic phenotypes including obesity. Lztfl1^-/- mice are hyperphagic and showed similar energy expenditure as WT littermates. The obese phenotype of Lztfl1-/- mice is caused by the loss of Lztfl1 in the brain but not in the adipocytes.Lztfl1-/- mice are leptin-resistant. Inactivation of Lztfl1 abolished phosphorylation of Stat3 in the LepRb signaling pathway in the hypothalamus upon leptin stimulation. Deletion of Lztfl1 had no effect on LepRb membrane localization. Furthermore, we observed that Lztfl1-/- mouse embryonic fibroblasts （MEFs） have significantly longer cilia than WT MEFs. We identified several proteins that potentially interact with Lztfl1. As these proteins are known to be involved in regulation of actin/cytoskeleton dynamics, we suggest that Lztfl1 may regulate leptin signaling and ciliary structure via these proteins. Our study identified Lztfl1 as a novel player in the LepRb signaling pathway in the hypothalamus that controls energy homeostasis.