Brain interleukin-18 control of food intake and energy expenditure

脑白细胞介素 18 控制食物摄入和能量消耗

基本信息

批准号：
8373865
负责人：
BRUNO CONTI
金额：
$ 37.9万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-17 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8373865
关键词：
Adipocytes Adult Anorexia Appetite Depressants Behavioral Body part Brain Cachexia Data Dependence Development Diet Disease Eating Energy Metabolism Fatty acid glycerol esters Fever Food Energy Future Genes Genetic Heterozygote Homeostasis Hormones Human Human Genetics Hyperphagia Hypothalamic structure Immune Immune system Inflammatory Insulin Resistance Interleukin-18 Knock-out Leptin Lesion Lipopolysaccharides Malaise Metabolic Metabolic syndrome Molecular Morphologic artifacts Mus Mutant Strains Mice Neurons Obesity Overweight Pathway interactions Peripheral Phenotype Physiological Population Property Role Satiation Seminal Signal Transduction Single Nucleotide Polymorphism Site Synaptic Transmission Syndrome System Testing Therapeutic Weight cell type clinically relevant cytokine energy balance feeding innovation loss of function molecular site mouse model multidisciplinary mutant novel obesity risk obesity treatment offspring paraventricular nucleus receptor receptor binding research study response ventromedial hypothalamic nucleus wasting young adult

项目摘要

DESCRIPTION (provided by applicant): Data have accrued implicating interleukin-18 (IL-18), a cytokine discovered for its immune system-modulating properties, in the control of food intake and energy metabolism. We and others found that the IL-18 modulates energy homeostasis during adulthood in mice. Mice deficient in IL-18 (IL-18-/-) or its binding receptor subunit (IL-18Ra) develop maturity-onset obesity and insulin resistance. As young adults, before they become substantially overweight, IL-18-/- mice are fattier, show reduced energy expenditure, and overeat both low-fat and high-fat diets as compared to wildtype mice. Because heterozygote IL-18+/- mutant mice show an intermediate hyperphagic phenotype, the findings appear to be regulatory, rather than an artifact of non- specific developmental "lesion" effects. Converse to these loss-of-function studies, central administration of IL- 18 suppresses food intake and weight regain in hungry mice as potently as does the adipocyte hormone leptin and does so without producing the adverse malaise, fever or HPA-axis activation classically associated with proinflammatory cytokine-driven "sickness" anorexia. Human genetic studies have recently identified single nucleotide polymorphisms (SNPs) in the gene for IL-18 or its receptor associated with increased risk for obesity and metabolic syndrome disorders. IL-18 and its receptors are constitutively expressed in the hypothalamus, with levels increased by peripheral immune challenge. Therefore, the guiding hypothesis tested in the present application is that central IL-18 systems can control food intake and energy expenditure. Translationally, this function would make IL-18 a clinically relevant target for sickness syndrome/cachexia. Moreover, because IL-18 administration does not share "sickness syndrome" effects of the pro-inflammatory system, exogenous IL-18 may have translational relevance as an anti-obesity treatment. To test this hypothesis, the present interdisciplinary proposal combines complementary but distinct, expertise of two PI's to determine mechanistically how central IL-18-responsive systems modulate food intake, energy expenditure, and, ultimately, adiposity. Experiments in two Specific Aims combine global and Cre/lox-targeted genetic loss- of-function mouse models deficient in IL-18 or the IL-18R; classic molecular, pharmacological, and physiologic approaches; and innovative behavioral analyses. AIM 1 seeks to identify physiologic and receptor mechanisms for central IL-18 control of food intake and energy expenditure. The potency and IL-18R- dependence of central IL-18 reductions in food intake and increases in energy expenditure will be determined. Pair-feeding is used to determine the functional role of excess food intake in the obesity of IL-18 null mutants. Feeding microstructure analysis is used to explore whether IL-18 modulates meal size or post-meal satiety in controlling food intake. Finally, the influence of diet-induced obesity on molecula expression and functional sensitivity of the central IL-18 system is determined. AIM 2 seeks to identify central sites and molecular mechanisms of IL-18 action on energy homeostasis. Expt. 2.1 will yield key information regarding the cell types the express IL-18 and its cognate receptors within the hypothalamus under basal conditions and following peripheral immune challenge (lipopolysaccharide), histochemically differentiating neuronal from glial populations, modes of fast synaptic transmission, and neuroanatomical interactions with anorectic pathways implicated in cytokine anorexia. In Expts 2.2-2.3, Cre/lox targeting will be used to generate mice that lack IL- 18R subunits selectively in the paraventricular nucleus of the hypothalamus (PVN) and the ventromedial hypothalamic nucleus (VMH). Studies will involve phenotyping the offspring for energy balance parameters to allow comparison with results obtained in the global knockout and also to determine whether the site-specific deletion alters feeding or metabolic responses to central IL-18 administration. The studies provide a powerful test of the functional significance of IL-18/IL-18R systems in the PVN and VMH for the control of food intake and energy expenditure. Collectively, the results will provide seminal data regarding the sites and mechanisms of action by which IL-18 systems modulate food intake and energy expenditure. Such information will be key for beginning to understand the pathophysiologic and potential therapeutic relevance of central IL-18 signaling for disorders of energy homeostasis, such as obesity or cachexia. PUBLIC HEALTH RELEVANCE: A better understanding of novel mechanisms with therapeutic relevance for pathological "sickness" disorders of negative energy balance (e.g., cachexia wasting, sickness anorexia) or of positive energy balance (e.g., obesity, metabolic syndrome disorders) is urgently needed. Data have accrued implicating interleukin-18 (IL- 18), a cytokine discovered for its immune system-modulating properties, in the control of food intake and energy metabolism. In order to elucidate the pathophysiologic and potential therapeutic relevance of central IL- 18 signaling for disorders of energy homeostasis., the present multidisciplinary proposal combines complementary but distinct, expertise of two PI's to determine mechanistically how central IL-18-responsive systems modulate food intake, energy expenditure, and, ultimately, adiposity.

描述（由申请人提供）：数据涉及白介素-18（IL-18），这是一种因其免疫系统调节特性而发现的细胞因子，以控制食物摄入和能量代谢。我们和其他人发现，IL-18在小鼠成年期间调节能量稳态。缺乏IL-18（IL-18 - / - ）或其结合受体亚基（IL-18RA）的小鼠会产生成熟度 - 肥胖和胰岛素抵抗。作为年轻人，与野生型小鼠相比，IL-18 - / - 小鼠在实质上超重之前，IL-18-/ - 小鼠表现出降低的能量消耗，并且低脂和高脂饮食过度。由于杂合子IL-18 +/-突变小鼠显示出中间的倍感表型，因此发现似乎是调节性的，而不是非特异性发育“病变”效应的伪像。与这些功能丧失研究相反，中央给药IL-18与脂肪细胞激素瘦素一样有效地抑制饥饿的小鼠的食物摄入和体重，并且在不产生与促炎性细胞动物驱动器驱动的“疗法” Anorexia的脂肪症，发烧或HPA轴激活的情况下这样做。人类遗传研究最近鉴定出IL-18基因中的单核苷酸多态性（SNP）或与肥胖和代谢综合征疾病风险增加有关的受体。 IL-18及其受体在下丘脑中的组成型表达，其水平通过外周免疫攻击而提高。因此，在本应用程序中检验的指导假设是中央IL-18系统可以控制食品摄入和能量消耗。翻译上，此功能将使IL-18成为疾病综合征/恶病质的临床相关靶标。此外，由于IL-18给药不具有促炎系统的“疾病综合征”影响，因此外源性IL-18可能具有转化的相关性作为抗肥胖治疗。为了检验这一假设，目前的跨学科提案结合了两个PI的补充但独特的知识，以机理的方式确定中央IL-18反应系统如何调节食物的摄入量，能源消耗以及最终的肥胖。两个特定目的的实验结合了全球和CRE/LOX靶向的遗传损失 - 功能小鼠模型缺乏IL-18或IL-18R；经典的分子，药理和生理方法；和创新的行为分析。 AIM 1旨在鉴定中央IL-18控制食物摄入和能量消耗的生理和受体机制。将确定中央IL-18降低食物摄入量和能量消耗增加的效力和IL-18R-依赖性。配对喂养用于确定多余食物摄入量在IL-18空突变体肥胖中的功能作用。喂养微观结构分析用于探索IL-18在控制食物摄入量时是否调节进餐大小或餐后饱腹感。最后，确定了饮食诱导的肥胖对分子表达和中枢IL-18系统功能敏感性的影响。 AIM 2旨在确定IL-18对能量稳态作用的中央部位和分子机制。 expt。 2.1将产生有关细胞类型的关键信息，在基础条件下和下丘脑内的表达IL-18及其同源受体，并在外周免疫挑战（脂多糖），组织化学上的神经元与神经元之间的神经元不同，快速突触传播的模式以及与anorect anore cytokia anore cytokia的含义。在expts 2.2-2.3中，将使用CRE/LOX靶向来产生在下丘脑（PVN）和腹膜下丘脑下丘脑核（VMH）中选择性地缺乏IL-18R亚基的小鼠。研究将涉及对能量平衡参数的后代表型，以允许与全球敲除中获得的结果进行比较，并确定特定地点的缺失是否会改变对中央IL-18给药的喂养或代谢反应。这些研究为PVN和VMH中IL-18/IL-18R系统的功能意义提供了有力的测试，以控制食物摄入和能量消耗。结果总的来说，结果将提供有关IL-18系统调节食物摄入和能量消耗的作用位点和机制的精确数据。这些信息将是开始了解中央IL-18信号对能量稳态疾病（例如肥胖或恶病质）的病理生理和潜在治疗相关性的关键。公共卫生相关性：更好地理解与病理学“疾病”负能量平衡（例如卡希克西氏症浪费，疾病厌食）或正能量平衡（例如肥胖，代谢综合征疾病）的治疗性“疾病”疾病的治疗相关性的更好理解。数据累积了介入的白介素18（IL-18），这是一种因其免疫系统调节特性而发现的细胞因子，以控制食物摄入和能量代谢。为了阐明中央IL-18信号对能量稳态疾病的病理生理和潜在的治疗相关性。目前的多学科建议结合了互补的，但截然不同的，两种PI的专业知识，以机械的方式确定中央IL-18-响应系统如何调节食物的摄入量，最终如何调节食品，最终以及额外的量。