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）：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调节小鼠成年期的能量稳态。缺乏IL-18 （IL-18-/-）或其结合受体亚基（IL-18Ra）的小鼠会发生成熟型肥胖和胰岛素抵抗。与野生型小鼠相比，成年后的IL-18-/-小鼠在体重大幅超重之前，会更胖，能量消耗减少，低脂和高脂饮食都会过量。因为杂合子IL-18+/-突变小鼠表现出一种中间的贪食表型，这些发现似乎是调节的，而不是非特异性发育“病变”效应的人工产物。与这些功能丧失的研究相反，在饥饿小鼠中，IL- 18的中央管理与脂肪细胞激素瘦素一样有效地抑制食物摄入和体重恢复，并且不会产生不良的不适，发烧或hpa轴激活，这通常与促炎细胞因子驱动的“疾病”性厌食症有关。人类遗传学研究最近发现，IL-18基因或其受体的单核苷酸多态性（snp）与肥胖和代谢综合征疾病的风险增加有关。IL-18及其受体在下丘脑中组成性表达，其水平因外周免疫攻击而升高。因此，在本应用中测试的指导性假设是中央IL-18系统可以控制食物摄入和能量消耗。翻译上，这一功能将使IL-18成为疾病综合征/恶病质的临床相关靶点。此外，由于IL-18给药不具有促炎系统的“疾病综合征”效应，外源性IL-18作为抗肥胖治疗可能具有翻译相关性。为了验证这一假设，目前的跨学科建议结合了两个PI的互补但不同的专业知识，以确定中央il -18响应系统如何调节食物摄入，能量消耗，并最终调节肥胖。在两种特异性目标中结合全局和Cre/lox靶向的IL-18或IL-18R缺失的基因功能丧失小鼠模型的实验；经典的分子、药理学和生理学方法；以及创新的行为分析。AIM 1旨在确定中央IL-18控制食物摄入和能量消耗的生理和受体机制。在食物摄入减少和能量消耗增加的过程中，中枢IL-18的效力和IL-18R依赖性将被确定。配对喂养用于确定过量食物摄入在IL-18无突变体肥胖中的功能作用。通过摄食微观结构分析，探讨IL-18是否通过调节膳食大小或餐后饱腹感来控制摄食。最后，确定饮食性肥胖对中枢IL-18系统分子表达和功能敏感性的影响。AIM 2旨在确定IL-18作用于能量稳态的中心位点和分子机制。2.1将提供关于细胞类型的关键信息，在基础条件下和外周免疫挑战（脂多糖）下，下丘脑内表达IL-18及其同源受体，组织化学区分神经元和胶质群体，快速突触传递模式，以及与细胞因子厌食症相关的厌食途径的神经解剖学相互作用。在实验2.2-2.3中，Cre/lox靶向将用于在下丘脑室旁核（PVN）和下丘脑腹内侧核（VMH）中选择性地产生缺乏IL- 18R亚基的小鼠。研究将涉及后代的能量平衡参数表型，以便与全球敲除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给药的喂养或代谢反应。这些研究为IL-18/IL-18R系统在PVN和VMH中控制食物摄入和能量消耗的功能意义提供了有力的检验。总的来说，这些结果将提供关于IL-18系统调节食物摄入和能量消耗的位置和作用机制的开创性数据。这些信息将是开始理解中央IL-18信号与能量稳态紊乱（如肥胖或恶病质）的病理生理和潜在治疗相关性的关键。