Brain integration of adiposity and satiety signals in the control of food intake

大脑整合肥胖和饱腹感信号来控制食物摄入

• 批准号: 8119759
• 负责人: Diana L Williams
• 金额: $ 24.65万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8119759
• 关键词: Accounting; Address; Adipose tissue; Agonist; Animals; Anorexia; Area; Award; Behavioral; Biological; Biological Factors; Body Weight; Body Weight decreased; Body fat; Brain; Brain Stem; Brain region; Cell Nucleus; Cells; Cholecystokinin; Cholecystokinin A Receptor; Cholecystokinin Receptor; Complex; Data; Defect; Detection; Devazepide; Development; Diet; Dorsal; Dose; Eating; Enteroendocrine Cell; Exhibits; Experimental Models; FOS gene; Fasting; Fat-Restricted Diet; Fatty acid glycerol esters; Food; Food Intake Regulation; Gastrointestinal tract structure; Gene Mutation; Genetic; Glucagon; Goals; Hormones; Human; Hyperphagia; Hypothalamic structure; Infusion procedures; Ingestion; Injection of therapeutic agent; Intake; Intraperitoneal Injections; Laboratories; Lead; Leptin; Leptin resistance; Light; Maintenance; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolic Diseases; Microinjections; Modeling; Mus; Nature; Neural Pathways; Neuraxis; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nucleus solitarius; Nutrient; Obesity; Pathogenesis; Pathway interactions; Patients; Pattern; Peptides; Perception; Peripheral; Pharmacological Treatment; Phase; Phosphorylation; Physiological; Plasma; Play; Population; Prevention; Process; Prosencephalon; Public Health; Rattus; Receptor Activation; Receptor Gene; Regulation; Reporting; Research; Rodent; Role; Satiation; Satiety Response; Signal Transduction; Site; Small Intestines; Stomach; Structure of area postrema; Structure of nucleus infundibularis hypothalami; Suggestion; Techniques; Testing; Time Study; Treatment Efficacy; Vagus nerve structure; Ventricular; Weight Gain; Work; base; behavioral pharmacology; cholecystokinin 9; common treatment; dorsal motor nucleus; energy balance; exenatide; feeding; gastrointestinal; gene therapy; glucagon-like peptide; hindbrain; improved; insight; leptin receptor; neural circuit; neuromechanism; neuroregulation; prevent; receptor; receptor expression; relating to nervous system; research study; response

Obesity and related metabolic disorders have become a tremendous public health problem. This proposal Investigates the neural circuitry that Integrates input from the adiposity hormone leptin and the gut-derived satiety signals cholecystokinin (CCK) and glucagon-like peptlde-1 (GLP-1), and the physiological relevance ofthe interactions between these signals for the control of food Intake and body weight. Available data support the hypothesis that the adiposity hormone leptin reduces food Intake in part by enhancing satiety responses to gastrointestinal signals, Includingj CCK. We have recently determined that leptin Interacts In a sirnilar rrianrier with GLP-1, but our data suggest that the leptin-CCK and leptin-GLP-1 interactions are mediated through different neuronal pathways, Here, we propose to Identify and compare brain areas In which leptin detection Is sufficient to enhance the responses to GLP-1 and CCK, using site-speclfic microinjections and gene therapy In normal rats and rats that lack leptin receptors due to genetic mutation. Next, we will Investigate whether leptin reduces food Intake and enhances the satiety response to gastrointestinal nutrients in part by modulating rats' sensitivity to endogenously released GLP-1 or CCK. Finally, we will determine whether altered sensitivity to GLP-i or CCK plays a role in the pathogenesis of diet-Induced obesity when rats are maintained on a high-fat diet, which produces leptin resistance, together, these studies will help to clarify how changes In body fat stores lead to compensatory adjustments in meal size, as well as how defects In this process may lead to obesity and metabolic disorders, and thus have the potential to significantly advance our understanding ofthe neural control of feeding and body weight.

肥胖和相关的代谢紊乱已成为一个巨大的公共卫生问题。该提案研究了整合来自肥胖激素瘦素和肠源性饱腹感信号胆囊收缩素 (CCK) 和胰高血糖素样肽-1 (GLP-1) 输入的神经回路，以及这些信号之间相互作用与控制食物摄入和体重的生理相关性。现有数据支持这样的假设：肥胖激素瘦素部分通过增强对胃肠道信号（包括 CCK）的饱腹感反应来减少食物摄入。我们最近确定瘦素在sirnilar rrianrier中与GLP-1相互作用，但我们的数据表明瘦素-CCK和瘦素-GLP-1相互作用是通过不同的神经元通路介导的，在这里，我们建议使用位点特异性显微注射和基因治疗在正常大鼠和大鼠中识别和比较瘦素检测足以增强对GLP-1和CCK反应的大脑区域。 由于基因突变而缺乏瘦素受体的大鼠。 接下来，我们将研究瘦素是否会减少食物摄入并增强饱腹感反应 胃肠道营养部分是通过调节大鼠对内源性释放的 GLP-1 或 CCK 的敏感性来实现的。 最后，我们将确定当大鼠维持高脂饮食时，对 GLP-i 或 CCK 的敏感性改变是否在饮食引起的肥胖发病机制中发挥作用，这会产生瘦素抵抗，同时，这些研究将有助于阐明体内脂肪储存的变化如何导致膳食量的代偿性调整，以及该过程中的缺陷如何可能导致肥胖和代谢紊乱，从而有可能显着推进 我们对进食和体重的神经控制的理解。

项目成果

Neural integration of satiation and food reward: role of GLP-1 and orexin pathways.

• DOI: 10.1016/j.physbeh.2014.03.013
• 发表时间: 2014-09
• 期刊: Physiology & behavior
• 影响因子: 2.9
• 作者: Williams DL

Expecting to eat: glucagon-like peptide-1 and the anticipation of meals.

期待进食：胰高血糖素样肽-1 和对进餐的期待。

• DOI: 10.1210/en.2009-1372
• 发表时间: 2010
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Williams,DianaL

Glucagon-like peptide 1 receptors in nucleus accumbens affect food intake.

• DOI: 10.1523/jneurosci.3262-11.2011
• 发表时间: 2011-10-12
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Dossat AM;Lilly N;Kay K;Williams DL
• 通讯作者: Williams DL

Hindbrain orexin 1 receptors influence palatable food intake, operant responding for food, and food-conditioned place preference in rats.

• DOI: 10.1007/s00213-013-3248-9
• 发表时间: 2014-01
• 期刊: PSYCHOPHARMACOLOGY
• 影响因子: 3.4
• 作者: Kay, Kristen;Parise, Eric M.;Lilly, Nicole;Williams, Diana L.
• 通讯作者: Williams, Diana L.

Oxytocin action in the ventral tegmental area affects sucrose intake.

• DOI: 10.1016/j.brainres.2013.03.026
• 发表时间: 2013-06-04
• 期刊: Brain research
• 影响因子: 2.9
• 作者: Mullis K;Kay K;Williams DL
• 通讯作者: Williams DL