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

• 批准号: 10439964
• 负责人: Min Hyun Kim
• 金额: $ 2.42万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-10 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439964
• 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; Phenotype; Phosphorylation; Plasma; Property; Regulation; Reporter; Ribosomal Proteins; Rodent; STAT3 gene; Signal Transduction; Slug protein; Techniques; Testing; Transcription Repressor; 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; obese patients; obesity prevention; obesity treatment; overexpression; promoter; relating to nervous system; slug; social

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，例如血脂异常，心血管疾病，胰岛素抵抗， 和2型糖尿病。肥胖已经成为沉重的社会负担，因为全球约有5亿成人 被认为肥胖。瘦素是维持能量稳态和体重的关键脂肪因子 调节喂养行为和能量消耗。在大多数情况下，血浆瘦素水平异常高 在肥胖症患者中，比正常个体（瘦素耐药性），因此额外的瘦素的给药未能 扭转肥胖状态。了解瘦素耐药性的分子机理和调节至关重要 用于有效的瘦素疗法。在搜索影响瘦素敏感性和体重的因素时，我们 已识别出的slug（也称为SNAI2）表观遗传因子。 SLUG引起脱乙酰化，脱甲基化和/或甲基化 H3K4，H3K9和/或H3K27，从而抑制其靶基因。但是，它在大脑中的作用并非 探索。初步数据表明表达表达的神经元在一个子集中高度富集 下丘脑神经元与调节能量平衡和体重有关。高脂饮食（HFD） 下丘脑sl的水平和下丘脑slug+神经元的数量增加。重要的是，两者俩 全球（KO）和LEPR+细胞特异性弹药敲除（LKO）小鼠抵抗HFD诱导的瘦素耐药性，肥胖症， 2型糖尿病和非酒精性脂肪肝病，由于能量消耗的增加。我的工作 假设是下丘脑slug+神经元，尤其是slug+ Lepr+亚群是枢纽 能量代谢回路。在分子水平上，SLUG表观遗传调节关键分子的表达 参与瘦素信号传导。为了检验这一假设，我已经开发了两个目标。目的1是描绘解剖学， Slug+神经元的化学和功能特性。要确定下丘脑sl+神经回路，我将绘制 使用CRE/LOXP依赖和基于病毒的神经跟踪的SLUG+神经元的上游和下游 技术。此外，我将确定slug+神经元表达的签名神经肽以获得洞察力 slug+电路控制能量代谢和体重的机制。此外，我会的 使用化学发生方法来定义SLUG+神经元的独特功能。目标2是审问 Slug控制SLUG+ LEPR+电路调节能量平衡的能力的分子机制 和体重。我的初步数据表明，SLUG可能会抑制瘦素信号，导致瘦素 反抗。为了扩展这些令人兴奋的发现，我将评估LKO小鼠中的下丘脑瘦素信号传导。我会测试 Slug表观遗传抑制瘦素受体的表达，导致瘦素耐药的假设。 此外，我将分析下丘脑slug+神经元的翻译曲线，以便全面 了解slug+神经元行为。影响包括定义新颖的弹道和揭幕小说 瘦素耐药性的表观遗传调节。预计该项目的结果将导致新的治疗性 通过靶向下丘脑sl，预防肥胖/治疗策略。