The Role of Hypothalamic Slug in the Regulation of Leptin Sensitivity, Energy Balance, and Body Weight

下丘脑蛞蝓在瘦素敏感性、能量平衡和体重调节中的作用

基本信息

批准号：
10197297
负责人：
LIANGYOU RUI
金额：
$ 39万
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：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10197297
关键词：
Adipose tissue Affect Blood Glucose Body Temperature Body Weight Brain Cells Data Diabetes Mellitus Eating Energy Metabolism Epigenetic Process Equilibrium Fatty Liver Fatty acid glycerol esters Genes Genetic Genomics Glucose Goals High Fat Diet Histone Acetylation Homeostasis Human Hypothalamic structure Impairment Insulin Resistance Knock-out Knockout Mice Lead Leptin Leptin resistance Link Lysine Maintenance Mediating Metabolic Metabolic Diseases Metabolism Methods Methylation Molecular Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity Outcome Pathway interactions Predisposition Prevention Regulation Research Risk Factors Rodent Role SH2B gene Shapes Signal Transduction Slug protein Sympathetic Nervous System Temperature Testing Thermogenesis Time arm base cold temperature effective therapy energy balance epigenetic regulation feeding histone modification improved leptin receptor lipid metabolism nerve supply neurotransmission novel novel strategies nutrient metabolism obesogenic promoter receptor slug targeted treatment treatment strategy

项目摘要

Abstract (Description) Obesity is associated with leptin resistance, which limits the potential of leptin therapies. Leptin suppresses food intake and increases energy expenditure by activating its receptors (LepR) in the hypothalamic energy balance circuitry. The food intake arm of the energy balance circuitry has been extensively examined; however, the energy expenditure arm of the circuitry is poorly understood. Moreover, epigenetic reprograming of the hypothalamic energy expenditure circuits has not been explored in the setting of obesity. Leptin stimulates brown and beige adipose tissue thermogenesis, contributing to energy expenditure. Brown and beige fat are required for the maintenance of body temperature homeostasis in rodents, and they also protect against obesity through increasing energy expenditure in both rodents and humans. In preliminary studies, we found that high fat diet (HFD) feeding increases the level of hypothalamic Slug, a nuclear epigenetic factor. We demonstrated that Slug induces methylations and/or acetylation of histone 3 lysine 4 (H3K4) and H3K9, key forms of epigenetic remodeling, in several metabolic gene promoters. We showed that Slug suppresses the expression of Sh2b1, a positive regulator of leptin sensitivity, and stimulates the expression of SOCS3, a negative regulator of leptin signaling. Importantly, LepR+ cell-specific deletion of Slug in mice increases the sympathetic innervation of brown and beige fat, brown/beige fat thermogenesis, energy expenditure, and the body core temperature, but it does not affect food intake. LepR+ cell-specific Slug knockout mice resist HFD- induced leptin resistance, obesity, insulin resistance, and liver steatosis. Hence, we hypothesize that in obesity, aberrant hypothalamic Slug induces leptin resistance selectively in the energy expenditure arm by an epigenetic mechanism. Selective leptin resistance lowers the temperature setpoint, which in turn decreases the body core temperature and energy expenditure through lowering the sympathetic drive in brown/beige fat, thereby contributing to obesity progression. We will test these hypotheses in 3 Aims. Aim 1: Determine whether HFD feeding induces leptin resistance by inducing epigenetic reprograming of the hypothalamic Slug+LepR+ circuits via Slug. Aim 2: Determine whether HFD feeding impairs the leptin/temperature setpoint/SNS/brown/beige fat pathway by epigenetic mechanisms. Aim 3: Determine whether epigenetic regulation of the leptin/temperature setpoint/SNS/brown/beige fat pathway guides energy expenditure, body weight, and metabolism. This project is significant because it introduces the novel concepts of epigenetic reprograming of the hypothalamic energy balance circuits and regulation of obesity progression by the temperature setpoint and is expected to lead to new approaches in therapies targeting obesity.

摘要（描述）肥胖与瘦素抵抗有关，这限制了瘦素疗法的潜力。瘦素抑制通过激活下丘脑能量受体 (LepR) 来减少食物摄入并增加能量消耗平衡电路。能量平衡电路的食物摄入臂已被广泛检查；然而，人们对电路的能量消耗部分知之甚少。此外，表观遗传重编程尚未在肥胖情况下探索下丘脑能量消耗回路的变化。瘦素刺激棕色和米色脂肪组织产热，有助于能量消耗。棕色和米色脂肪是维持啮齿动物体温稳态所必需的，它们还可以保护通过增加啮齿动物和人类的能量消耗来对抗肥胖。在初步研究中，我们发现高脂肪饮食（HFD）喂养会增加下丘脑蛞蝓的水平，这是一种核表观遗传因子。我们证明 Slug 诱导组蛋白 3 赖氨酸 4 (H3K4) 和 H3K9 的甲基化和/或乙酰化，关键几种代谢基因启动子中的表观遗传重塑形式。我们证明了 Slug 抑制了 Sh2b1（瘦素敏感性的正调节因子）的表达，并刺激 SOCS3（瘦素敏感性的正调节因子）的表达瘦素信号的负调节因子。重要的是，小鼠中 LepR+ 细胞特异性删除 Slug 会增加棕色和米色脂肪的交感神经支配、棕色/米色脂肪产热、能量消耗和身体核心温度，但不影响食物摄入量。 LepR+细胞特异性Slug基因敲除小鼠可抵抗HFD- 诱发瘦素抵抗、肥胖、胰岛素抵抗和肝脂肪变性。因此，我们假设在肥胖，异常的下丘脑 Slug 通过以下方式选择性地在能量消耗臂中诱导瘦素抵抗表观遗传机制。选择性瘦素抵抗会降低温度设定点，从而降低通过降低棕色/米色脂肪的交感神经驱动来降低身体核心温度和能量消耗，从而促进肥胖的进展。我们将在 3 个目标中检验这些假设。目标 1：确定 HFD 喂养是否通过诱导下丘脑表观遗传重编程来诱导瘦素抵抗 Slug+LepR+ 电路通过 Slug 实现。目标 2：确定 HFD 喂养是否会损害瘦素/体温通过表观遗传机制设定点/SNS/棕色/米色脂肪途径。目标 3：确定表观遗传是否瘦素/温度设定点/SNS/棕色/米色脂肪途径的调节指导能量消耗、身体体重、新陈代谢。该项目意义重大，因为它引入了表观遗传学的新概念下丘脑能量平衡回路的重新编程和肥胖进展的调节温度设定点，预计将带来针对肥胖的治疗新方法。