Role of IKK-beta/NF-kappaB in hypothalamic dysregulation of energy balance

IKK-beta/NF-kappaB 在下丘脑能量平衡失调中的作用

• 批准号: 8105513
• 负责人: Dongsheng Cai
• 金额: $ 32.54万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8105513
• 关键词: Ablation; Animal Testing; Body Weight; Brain; Cells; Chronic; Data; Diet; Disease; Energy Metabolism; Fatty acid glycerol esters; Gene Delivery; Genes; Goals; Health; Homeostasis; Hyperphagia; Hypothalamic structure; IKBKB; Impairment; Inflammation; Inflammatory; Insulin; Insulin Resistance; Knowledge; Label; Leptin; Leptin resistance; Liver; Mediating; Mediator of activation protein; Metabolic; Modeling; Molecular; Mus; NF-kappa B; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nutritional; Obesity; Outcome; Overnutrition; Pathogenesis; Pathway interactions; Peripheral; Phenotype; Phosphotransferases; Prevention; Prevention strategy; Regulation; Reporter; Role; Series; Signal Transduction; Site; Staining method; Stains; Subfamily lentivirinae; Syndrome; Testing; Tissues; Transgenic Mice; Weight Gain; base; energy balance; in vivo; insulin signaling; lentiviral-mediated; mind control; mouse model; novel therapeutics; nutrition; offspring; prevent; transcription factor; uptake

DESCRIPTION (provided by applicant): The hypothalamus critically controls body weight and energy homeostasis. The Insulin and leptin pathways are most pivotal in the hypothalamic regulation of energy balance and therefore critical in the prevention against excessive energy accumulation and the associated obesity and type 2 diabetes (T2D). Recent advances show that persistent overnutrition induces hypothalamic insensitivity to insulin and leptin; however, the involved molecular basis remains unclear. Following our previous discovery that pro-inflammatory nuclear transcription factor NF-kB and its upstream activator IKK? are activated in peripheral tissues by overnutrition leading to local insulin resistance, this proposal will investigate the role of IKKb/NF-kB in the hypothalamic dysregulation of energy balance, and in particular, in relation to the loss of insulin and leptin sensitivity in the hypothalamus. Preliminary results show that a high-fat diet activates IKK?/NF-kB in mouse hypothalamus, while activation of IKKb/NF-kB induces hypothalamic insulin resistance. Animal tests further show that activation of IKK?/NF-kB in the mediobasal hypothalamus (MBH) induced weight gain, while the ablation of IKK? in a subtype of insulin/leptin-sensitive hypothalamic neurons protected against the dietary induction of obesity. Therefore, this proposal hypothesizes that chronic overnutrition activates IKK?/NF-kB in the hypothalamus, desensitizes hypothalamic neurons to insulin and leptin, and causes energy imbalance leading to obesity-T2D. This hypothesis predicts that suppressing hypothalamic IKKb could reverse these diseases. The 3 specific aims which will be pursued are as follows: (1) depict the effect of overnutrition on NF-kB in the insulin/leptin- sensitive MBH neurons; (2) study the role of IKK?/NF-kB on hypothalamic insulin and leptin resistance; (3) assess the metabolic outcomes of ablating IKK? site-specifically in the MBH neurons or cell-specifically in the most relevant subtypes of insulin/leptin sensitive neurons - AGRP and POMC neurons. To achieve these aims, a series of our established mouse models and approaches of site-directed gene manipulations will be empoyed to analyze NF-kB, insulin/leptin signaling, and the metabolic phenotypes. The completion of this study will advance our knowledge about the brain pathogenesis of obesity-T2D, provide a molecular basis for developing new therapeutic and preventive strategies, and also establish a new model to study the nutrition- inflammation axis in the brain underlying nutritional diseases. PUBLIC HEALTH RELEVANCE: Given the understanding that the promotion of obesity and type 2 diabetes (T2D) by overnutrition critically arises from the overnutrition-impaired brain regulation of energy balance, this project will investigate whether overnutrition triggers a pro-inflammatory pathway in the regulation center of the brain, leading to the regulatory insensitivity that promotes obesity-T2D, and whether suppressing this pathway could reverse or prevent both diseases. The successful completion of this project will be the very first to establish a molecular connection between overnutrition and the inflammation that underlies the brain control of obesity-T2D, and it will also provide new strategies to counteract these diseases by suppressing this inflammatory pathway in the brain.

描述（由申请人提供）：下丘脑严重控制体重和能量稳态。胰岛素和瘦素途径在下丘脑能量平衡的调节中最关键，因此对于预防能量积累的预防以及相关的肥胖和2型糖尿病（T2D）至关重要。最近的进步表明，持续的营养不良会诱导胰岛素和瘦素的下丘脑不敏感性。但是，涉及的分子基尚不清楚。在我们之前发现促炎性核转录因子NF-KB及其上游激活因子IKK之后？通过营养不良导致局部胰岛素抵抗激活在外围组织中，该提案将研究IKKB/NF-KB在能量平衡下丘脑失调中的作用，尤其是与下丘脑中胰岛素和瘦素敏感性的丧失有关。初步结果表明，高脂饮食在小鼠下丘脑中激活IKK？/NF-KB，而IKKB/NF-KB的激活会诱导下丘脑胰岛素耐药性。动物测试进一步表明，在中质下丘脑（MBH）中，IKK？/NF-KB的激活会诱导体重增加，而IKK的消融？在胰岛素/瘦素敏感的下丘脑神经元的亚型中，免受肥胖症的饮食诱导。因此，该提议假设慢性营养果在下丘脑中激活IKK？/nf-kb，使下丘脑神经元脱敏至胰岛素和瘦素，并导致能量失衡，从而导致肥胖症-T2D。该假设预测，抑制下丘脑IKKB可以扭转这些疾病。将要追求的3个特定目的如下：（1）描绘营养不良对NF-KB的影响在胰岛素/瘦素敏感的MBH神经元中； （2）研究IKK？/NF-KB对下丘脑胰岛素和瘦素耐药的作用； （3）评估消融IKK的代谢结果？特定于MBH神经元或细胞特定于胰岛素/瘦素敏感神经元的最相关亚型 - AGRP和POMC神经元。为了实现这些目的，将授权我们一系列已建立的小鼠模型和定位基因操纵的方法分析NF-KB，胰岛素/瘦素信号传导和代谢表型。这项研究的完成将促进我们对肥胖-T2D脑发病机理的了解，为开发新的治疗和预防策略提供了分子基础，还建立了一种新的模型来研究营养 - 基本营养疾病的营养 - 炎症轴。 PUBLIC HEALTH RELEVANCE: Given the understanding that the promotion of obesity and type 2 diabetes (T2D) by overnutrition critically arises from the overnutrition-impaired brain regulation of energy balance, this project will investigate whether overnutrition triggers a pro-inflammatory pathway in the regulation center of the brain, leading to the regulatory insensitivity that promotes obesity-T2D, and whether suppressing this pathway could reverse or prevent两种疾病。该项目的成功完成将是第一个建立营养不良与炎症之间的分子联系的，这是肥胖-T2D的大脑控制的基础，并且还将提供新的策略来通过抑制大脑中的这种炎症性途径来抵消这些疾病。