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

下丘脑 Slug (Snai2) 神经回路对体重、能量消耗和营养代谢的调节

基本信息

批准号：
9794000
负责人：
Min Hyun Kim
金额：
$ 6.5万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-10 至 2021-09-09
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9794000
关键词：
Ablation Adenoviruses Adipose tissue Adult Affect Anatomy Antibodies Behavior Binding Body Weight Brain Cardiovascular Diseases Cells Chemicals Communication Cre-LoxP Data Deacetylation Defect Dyslipidemias Eating Energy Metabolism Enterobacteria phage P1 Cre recombinase Enzymes Epigenetic Process Feeding behaviors Fibrinogen Genes Health High Fat Diet Homeostasis Hypothalamic structure Individual Insulin Resistance Knock-out Knockout Mice Lead Leptin Leptin resistance Maps Mediating Medical Care Costs Messenger RNA Metabolic Diseases Metabolism Methods Methylation Modeling Molecular Molecular Mechanisms of Action Mus Neurons Neuropeptides Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Outcome Patients Phenotype Phosphorylation Plasma Property Regulation Reporter Ribosomal Proteins Rodent STAT3 gene Signal Transduction Slug protein Techniques Testing Transcription Repressor/Corepressor Viral Weight Gain adipokines base brain tissue demethylation designer receptors exclusively activated by designer drugs energy balance epigenetic regulation feeding insight leptin receptor mRNA Expression mind control neural circuit non-alcoholic fatty liver disease novel novel therapeutic intervention nutrient metabolism obesity prevention obesity treatment overexpression promoter relating to nervous system slug social

项目摘要

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.

项目摘要肥胖会产生不良健康后果，如血脂异常、心血管疾病、胰岛素抵抗、和 2 型糖尿病。肥胖已成为沉重的社会负担，目前全球约有 5 亿成年人被认为是肥胖。瘦素是维持能量稳态和体重的关键脂肪因子调节进食行为和能量消耗。在大多数情况下，血浆瘦素水平异常升高肥胖患者的比例高于正常人（瘦素抵抗），因此额外施用瘦素无法扭转肥胖状态。了解瘦素抵抗的分子机制和调控至关重要以获得有效的瘦素疗法。在寻找影响瘦素敏感性和体重的因素期间，我们鉴定出 Slug（也称为 Snai2）表观遗传因子。 Slug 引发脱乙酰化、脱甲基化和/或甲基化 H3K4、H3K9 和/或 H3K27，从而抑制其靶基因。然而，其在大脑中的作用尚未被证实。探索过。初步数据表明，表达 Slug 的神经元在以下子集中高度丰富：下丘脑神经元参与调节能量平衡和体重。高脂肪饮食（HFD）增加下丘脑 Slug 的水平和下丘脑 Slug+ 神经元的数量。重要的是，两者 global (KO) 和 LepR+ 细胞特异性 Slug 敲除 (LKO) 小鼠可抵抗 HFD 诱导的瘦素抵抗、肥胖、由于能量消耗增加，导致 2 型糖尿病和非酒精性脂肪肝。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表观遗传调控关键分子的表达参与瘦素信号传导。为了检验这个假设，我制定了两个目标。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，我将绘制使用依赖于 Cre/loxp 和基于病毒的神经追踪来分析 Slug+ 神经元的上游和下游技术。此外，我将识别 Slug+ 神经元表达的特征神经肽，以获得深入了解研究 Slug+ 电路控制能量代谢和体重的机制。此外，我将使用化学遗传学方法定义 Slug+ 神经元的独特功能。目标2是询问 Slug 控制 Slug+LepR+ 电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 Slug 可能会抑制瘦素信号传导，从而导致瘦素反抗。为了扩展这些令人兴奋的发现，我将评估 LKO 小鼠的下丘脑瘦素信号传导。我会测试 Slug 表观遗传学抑制瘦素受体的表达，从而导致瘦素抵抗的假设。此外，我将分析下丘脑 Slug+ 神经元的翻译特征，以便全面了解了解 Slug+ 神经元行为。影响包括定义新颖的 Slug 电路并推出新颖的瘦素抵抗的表观遗传调控。该项目的成果预计将带来新的治疗方法通过针对下丘脑 Slug 来预防/治疗肥胖的策略。