Leptin, GABAergic Neurons and the Feedback / Feedforward Regulation of Energy Balance

瘦素、GABA能神经元与能量平衡的反馈/前馈调节 弓状核(ARC)中的神经元，尤其是AgRP和POMC神经元，在调节 能量平衡。他们接收关于脂肪储存当前状态的反馈信息(通过瘦素)和 关于未来的“前馈”信息，能源平衡的预期变化。神经机制 然而，负责反馈和前馈调节的人是未知的。之前的研究已经 提示GABA能神经元在ARC传递反馈调节中起重要作用，在 背内侧下丘脑(DMH)在传递前馈调节中的作用。关于反馈调节， 由于缺乏对ARC中“未知”神经元的了解，进展受到了阻碍。在……里面 简而言之，我们缺少一份“零件清单”。最近，利用单神经元转录组学，我们发现了许多新的 ARC中的GABA能神经元，包括一些表达LEPR的神经元(Campbell JN等人，NAT Neurosci， 2017年)。在这些发现的基础上，目标1和目标2将解决反馈调节机制。目标3 将扩大我们的发现，即vDMH GABA能神经元介导AgRP神经元的前馈调节。 目的1：利用单神经元转录转录技术评价瘦素对急性淋巴细胞白血病基因表达的影响 ARCLepr和vDMHLepr神经元亚型。通过从所有LEPR表达的神经元中捕获细胞核 Arc和vDMH，并在单核水平上研究了全基因组对瘦素的转录反应，这 目的将确定瘦素在LEPR表达神经元的所有亚型中的细胞类型特异性转录效应。 目的：研究新型ARCGAB能神经元在调节能量平衡中的作用。这个 将研究以下神经元：表达Lepr的GABA能ARCTrh/CXCL12神经元-表达 在ARC，LEPR表达的GABA能ARCTbx19神经元中LEPR水平最高-它们是 在转录上类似于瘦素调节的控制能量消耗的RIP-CRE神经元，GABA能 ARCTrh-Lef1神经元--富含与人体体重指数(BMI)相对应的转录本 GABA能ARCSST神经元--在转录上类似于AgRP神经元和 因此很可能共享功能，最后是GABA能ARCHtr3b神经元-它们在转录上是不同的 但是表达有趣的，独特的离子亲性5-羟色胺受体，5-HT3AB。 目标3：为了确定食物线索的“前馈”调节达到vDMHLepr的方式- GABA的agrp电路。我们和其他人意外地发现，AgRP神经元除了 受反馈信号的调节，如瘦素，也受感官信号的快速调节，这些感官信号可以“预测”食物 消费。重要的是，这至少部分是由vDMHLepr-GABA能神经元介导的，这些神经元突触到 AgRP神经元。这一目的是为了寻找这一规定的根源。我们的研究表明，在功能上， 下丘脑外侧区有明显的谷氨酸能神经元亚群。

Leptin, GABAergic Neurons and Feedback / Feedforward Regulation of Energy Balance Neurons in the arcuate nucleus (ARC), especially AgRP and POMC neurons, play key roles in regulating energy balance. They receive feedback information on the current status of fat stores (via leptin) and “feedforward” information on future, anticipated changes in energy balance. The neural mechanisms responsible for feedback and feedforward regulation, however, are unknown. Previous studies have suggested an important role for GABAergic neurons; in the ARC in relaying feedback regulation, and in the dorsomedial hypothalamus (DMH) in relaying feedforward regulation. With regards to feedback regulation, progress has been hampered by lack of knowledge regarding “unknown” neurons that reside in the ARC. In short, we have lacked a “parts list”. Recently, using single neuron transcriptomics, we discovered many novel GABAergic neurons in the ARC, including some which express LEPRs (Campbell JN et al., Nat Neurosci, 2017). Building on these discoveries, Aims 1 and 2 will address mechanisms of feedback regulation. Aim 3 will extend our discovery that vDMH GABAergic neurons mediate feedforward regulation of AgRP neurons. Aim 1: To use single neuron transcriptomics to assess leptin’s effects on gene expression in all subtypes of ARCLepr and vDMHLepr neurons. By capturing nuclei from all LEPR-expressing neurons in the ARC and vDMH, and looking at genome-wide transcriptional responses to leptin at the single nuclei level, this Aim will identify cell type-specific transcriptional effects of leptin in all subtypes of LEPR-expressing neurons. Aim 2: To investigate the role of novel ARCGABAergic neurons in regulating energy balance. The following neurons will be studied: LEPR-expressing, GABAergic ARCTrh/Cxcl12 neurons – which express the highest level of LEPRs in the ARC, LEPR-expressing, GABAergic ARCTbx19 neurons – which are transcriptionally similar to the leptin-regulated “RIP-Cre” neurons that control energy expenditure, GABAergic ARCTrh-Lef1 neurons – which are enriched for transcripts corresponding to human body mass index (BMI) GWAS-linked loci, GABAergic ARCSST neurons – which are transcriptionally similar to AgRP neurons and thus likely to share functions, and finally GABAergic ARCHtr3b neurons – which are transcriptionally distinct but express the interesting, unique ionotropic serotonin receptor, 5-HT3AB. Aim 3: To determine the means by which food-cue, “feedforward” regulation reaches the vDMHLepr- GABAergic à AgRP circuit. We and others unexpectedly found that AgRP neurons, in addition to being regulated by feedback signals such as leptin, are also regulated rapidly by sensory cues that “anticipate” food consumption. Importantly, this is mediated, at least in part, by vDMHLepr-GABAergic neurons which synapse onto AgRP neurons. This Aim seeks the source of this regulation. Our studies suggest a key role for a functionally distinct subset of glutamatergic neurons in the lateral hypothalamus.