Regulation of body weight, energy expenditure, and nutrient metabolism by hypothalamic Slug (Snai2) neural circuits

项目摘要 肥胖会产生不良的健康后果，如血脂异常、心血管疾病、胰岛素抵抗、 和2型糖尿病。肥胖已经成为一种沉重的社会负担，目前全球约有5亿成年人 被认为是肥胖。瘦素是维持能量平衡和体重的关键脂肪因子，通过 调节摄食行为和能量消耗。在大多数情况下，血浆瘦素水平异常高 肥胖患者的瘦素抵抗(瘦素抵抗)，因此额外注射瘦素不能 扭转肥胖状态。了解瘦素抵抗的分子机制及其调控是非常必要的。 有效的瘦素疗法。在寻找影响瘦素敏感性和体重的因素时，我们 确定了鼻塞(也称为SNAI2)表观遗传因素。鼻涕虫引起脱乙酰化、去甲基化和/或甲基化 H3K4、H3K9和/或H3K27，从而抑制其靶基因。然而，它在大脑中的作用并不是 探索过了。初步数据表明，表达鼻涕虫的神经元高度浓缩在 参与调节能量平衡和体重的下丘脑神经元。高脂肪饮食(HFD) 增加下丘脑Slug水平和下丘脑Slug+神经元的数量。重要的是，两者 Global(KO)和Lepr+细胞特异性Slug基因敲除(LKO)小鼠抵抗HFD诱导的瘦素抵抗、肥胖 2型糖尿病和非酒精性脂肪肝，这是由于能量消耗增加所致。我的工作 假设下丘脑Slug+神经元，特别是Slug+Lepr+亚群是 能量代谢回路。在分子水平上，Slug在表观遗传学上调节关键分子的表达。 参与瘦素信号的传递。为了检验这一假设，我提出了两个目标。目标1是描绘解剖结构， Slug+神经元的化学和功能特性。为了确定下丘脑Slug+神经回路，我将绘制 用Cre/loxP依赖和病毒为基础的神经示踪法研究Slug+神经元的上下游 技巧。此外，我还将鉴定Slug+神经元表达的标志性神经肽，以获得洞察力。 进入鼻涕虫+回路控制能量代谢和体重的机制。此外，我会 使用化学发生学方法定义鼻塞+神经元的不同功能。目标2是审问 SLUG控制SLUG+LEPR+回路调节能量平衡能力的分子机制 和体重。我的初步数据表明，鼻涕虫可能会抑制瘦素信号，导致瘦素的产生 抵抗。为了推广这些令人兴奋的发现，我将评估LKO小鼠的下丘脑瘦素信号。我要测试一下 鼻涕虫表观遗传学抑制瘦素受体表达，导致瘦素抵抗的假说。 此外，我还将分析下丘脑Slug+神经元的翻译图谱，以便全面了解 了解鼻涕+神经元的行为。其影响包括定义一种新的Slug电路和揭开小说的面纱 瘦素抵抗的表观遗传学调控。这一项目的结果有望带来新的治疗方法 通过靶向下丘脑鼻涕虫预防/治疗肥胖的策略。

Project Abstract Obesity produces adverse health consequences such as dyslipidemia, cardiovascular disease, insulin resistance, and Type 2 diabetes. Obesity has become a heavy social burden as about 500 million adults worldwide are now considered obese. Leptin is the critical adipokine that maintains energy homeostasis and body weight by modulating feeding behavior and energy expenditure. In most cases, plasma leptin levels are abnormally higher in obesity patients than in normal individuals (leptin resistance), thus administration of additional leptin fails to reverse the obese state. It is essential to understand the molecular mechanism and regulation of leptin resistance for the effective leptin therapies. During a search for factors that affect leptin sensitivity and body weight, we identified Slug (also called Snai2) epigenetic factor. Slug elicits deacetylation, demethylation, and/or methylation of H3K4, H3K9, and/or H3K27, thereby repressing its target genes. However, its action in the brain has not been explored. The preliminary data indicate that Slug-expressing neurons are highly enriched in a subset of hypothalamic neurons which are implicated in regulating energy balance and body weight. A high fat diet (HFD) increases both the levels of hypothalamic Slug and the number of hypothalamic Slug+ neurons. Importantly, both global (KO) and LepR+ cell-specific Slug knockout (LKO) mice resist HFD-induced leptin resistance, obesity, type 2 diabetes, and nonalcoholic fatty liver disease, owing to increasing energy expenditure. My working hypothesis is that hypothalamic Slug+ neurons, particularly the Slug+LepR+ subpopulations are the hub of the energy metabolism circuits. At the molecular level, Slug epigenetically regulates expression of key molecules involved in leptin signaling. To test this hypothesis, I have developed two aims. Aim 1 is to delineate the anatomic, chemical, and functional properties of Slug+ neurons. To determine hypothalamic Slug+ neural circuits, I will map the upstream and the downstream of Slug+ neurons using Cre/loxp-dependent and viral-based neural tracing techniques. In addition, I will identify signature neuropeptides expressed by Slug+ neurons in order to gain insight into the mechanism by which the Slug+ circuitry controls energy metabolism and body weight. Furthermore, I will define the distinct function of Slug+ neurons using chemogenetic approaches. Aim 2 is to interrogate the molecular mechanisms by which Slug controls the ability of the Slug+LepR+ circuits to regulate energy balance and body weight. My preliminary data suggests that Slug likely inhibits leptin signaling, leading to leptin resistance. To extend these exciting findings, I will assess hypothalamic leptin signaling in LKO mice. I will test the hypothesis that Slug epigenetically suppresses expression of leptin receptor, contributing to leptin resistance. Additionally, I will analyze the translational profile of hypothalamic Slug+ neurons in order to comprehensively understand Slug+ neuronal behavior. The impact includes defining a novel Slug circuitry and unveiling novel epigenetic regulation of leptin resistance. The outcomes of this project are expected to lead to new therapeutic strategies for obesity prevention/treatment by targeting hypothalamic Slug.