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

• 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
• 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

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）：已积累的数据表明白细胞介素 18 (IL-18) 是一种因其免疫系统调节特性而被发现的细胞因子，可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) 的小鼠会出现成熟期肥胖和胰岛素抵抗。作为年轻人，在体重大幅超重之前，IL-18-/- 小鼠与野生型小鼠相比更加肥胖，能量消耗减少，并且低脂和高脂饮食摄入过多。因为杂合子IL-18+/-突变小鼠表现出中间的贪食表型，所以这些发现似乎是调节性的，而不是非特异性发育“损伤”效应的人为因素。与这些功能丧失研究相反，IL-18的中央给药可以像脂肪细胞激素瘦素一样有效地抑制饥饿小鼠的食物摄入和体重恢复，并且不会产生通常与促炎细胞因子驱动的“疾病”厌食症相关的不良不适、发烧或HPA轴激活。人类遗传学研究最近发现 IL-18 或其受体基因中的单核苷酸多态性 (SNP) 与肥胖和代谢综合征风险增加相关。 IL-18 及其受体在下丘脑中组成型表达，其水平因外周免疫攻击而增加。因此，本申请中测试的指导假设是中央IL-18系统可以控制食物摄入和能量消耗。从转化上讲，这一功能将使 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”效应，因此外源性IL-18作为抗肥胖治疗可能具有转化相关性。为了检验这一假设，目前的跨学科提案结合了两位 PI 的互补但不同的专业知识，以机械地确定中央 IL-18 响应系统如何调节食物摄入、能量消耗以及最终的肥胖。两个特定目标的实验结合了缺乏 IL-18 或 IL-18R 的全局和 Cre/lox 靶向遗传功能丧失小鼠模型；经典的分子、药理学和生理学方法；和创新的行为分析。 AIM 1 旨在确定 IL-18 对食物摄入和能量消耗的中枢控制的生理和受体机制。将确定中央IL-18减少食物摄入和增加能量消耗的效力和IL-18R依赖性。配对喂养用于确定过量食物摄入在 IL-18 无效突变体肥胖中的功能作用。饲喂微观结构分析用于探索 IL-18 是否通过调节膳食量或餐后饱腹感来控制食物摄入。最后，确定饮食诱导的肥胖对中枢 IL-18 系统的分子表达和功能敏感性的影响。 AIM 2 旨在确定 IL-18 对能量稳态作用的中心位点和分子机制。出口。 2.1 将产生有关在基础条件下和外周免疫攻击（脂多糖）后下丘脑内表达 IL-18 及其同源受体的细胞类型、在组织化学上区分神经元与胶质细胞群、快速突触传递模式以及与细胞因子厌食症有关的厌食途径的神经解剖学相互作用的关键信息。在Expts 2.2-2.3中，Cre/lox靶向将用于产生在下丘脑室旁核(PVN)和下丘脑腹内侧核(VMH)中选择性缺乏IL-18R亚基的小鼠。研究将涉及对后代的能量平衡参数进行表型分析，以便与全局敲除中获得的结果进行比较，并确定位点特异性缺失是否会改变对中央 IL-18 给药的摄食或代谢反应。这些研究为 PVN 和 VMH 中 IL-18/IL-18R 系统对控制食物摄入和能量消耗的功能意义提供了有力的测试。总的来说，这些结果将提供有关 IL-18 系统调节食物摄入和能量消耗的作用位点和机制的重要数据。这些信息对于开始了解中央 IL-18 信号传导与能量稳态紊乱（如肥胖或恶病质）的病理生理学和潜在治疗相关性至关重要。 公共卫生相关性：迫切需要更好地了解与负能量平衡（例如恶病质消耗、病性厌食症）或正能量平衡（例如肥胖、代谢综合征）的病理性“疾病”障碍的治疗相关的新机制。已有数据表明白细胞介素 18 (IL-18) 是一种因具有免疫系统调节特性而被发现的细胞因子，可控制食物摄入和能量代谢。为了阐明中枢 IL-18 信号传导与能量稳态紊乱的病理生理学和潜在治疗相关性，目前的多学科提案结合了两个 PI 的互补但不同的专业知识，以从机制上确定中枢 IL-18 响应系统如何调节食物摄入、能量消耗以及最终的肥胖。