The Role of the Ghrelin System in the Metabolic Responses to Exercise

生长素释放肽系统在运动代谢反应中的作用

• 批准号: 10242072
• 负责人: Jeffrey M Zigman
• 金额: $ 48.65万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242072
• 关键词: Address; Adrenergic Receptor; Agonist; Appetite Stimulants; Binding; Biology; Blood Glucose; Body Weight; Body Weight decreased; Cachexia; Caloric Restriction; Cell physiology; Cells; Collection; Data; Desire for food; Eating; Electrophysiology (science); Energy Metabolism; Ensure; Exercise; Exhibits; Fasting; Fiber; Gases; Genetically Engineered Mouse; Goals; Health; Hormonal; Hormones; Hour; Hyperphagia; Hypothalamic structure; Internal Ribosome Entry Site; Knockout Mice; Link; Mediating; Mediator of activation protein; Metabolic; Metabolism; Modeling; Mus; Muscular Atrophy; Mutation; Neurons; Phenotype; Photometry; Physiological; Physiology; Plasma; Population; Positioning Attribute; Protocols documentation; Publishing; Role; Running; SF1; Signal Transduction; Site; Skeletal Muscle; Stomach; Sympathetic Nervous System; System; Testing; Therapeutic; Virus; Weight; Wild Type Mouse; designer receptors exclusively activated by designer drugs; endurance exercise; energy balance; exercise capacity; exercise training; exhaustion; ghrelin; ghrelin receptor; growth hormone secretagogue receptor; in vivo; insight; mouse model; mutant; neuronal excitability; novel; predictive modeling; preservation; receptor; receptor expression; reduced food intake; response; treadmill; weight gain prevention

PROJECT SUMMARY Exercise is often highly effective for prevention of weight gain, for prevention of weight regain after weight loss, and for weight loss, however the hormonal and neuronal mediators that influence the complicated and highly variable exercise-associated changes in appetite and food intake and the exercise-associated effects on energy expenditure and related physiology such as exercise endurance, are poorly understood. In the current proposal, we aim to investigate the role of the hormone ghrelin and its receptor, the growth hormone secretagogue receptor (GHSR), in mediating the effects of exercise on food intake as well as in mediating exercise endurance. The proposal follows up on recently published findings in mice demonstrating that exercise transiently raises circulating levels of the hormone ghrelin and that without the action of this increased ghrelin, post-exercise food intake and exercise endurance are both markedly diminished. The proposal uses a unique collection of genetically-engineered mouse models to investigate the mechanisms regulating exercise- induced ghrelin release and the neuronal sites and other mechanisms through and by which ghrelin and its receptor mediate metabolic responses to exercise and exercise endurance. In particular, we will determine if ghrelin-dependent or ghrelin-independent (constitutive) signaling via GHSRs is required for the metabolic responses to exercise by evaluating the effects of ghrelin deletion and a GHSR mutation (which eliminates GHSR constitutive activity) on food intake, energy expenditure, neuronal excitability, and exercise endurance. We will use a mouse model lacking β1-adrenergic receptors exclusively in ghrelin cells to determine if activation of these ghrelin cell β1-adrenergic receptors, as induced by the sympathoadrenal system, is required for the ghrelin response to exercise. We also will use mice lacking GHSRs selectively from arcuate hypothalamic AgRP neurons or ventromedial hypothalamic SF1 neurons and mice with chemogenetically- inhibited mediobasal hypothalamic GHSR-expressing neurons to determine if those populations of hypothalamic neurons mediate the exercise-associated effects of the ghrelin system on metabolism and exercise endurance. Our studies will provide fundamental insight into the metabolic effects of exercise, exercise endurance, arcuate hypothalamic AgRP and POMC neuronal excitability, ghrelin cell physiology, and ghrelin action. Ultimately, we hope that studying the role of the ghrelin system in the metabolic responses to exercise may allow us to determine and therapeutically harness the mechanisms by which exercise promotes whole-body health.

项目总结 运动对预防体重增加、防止减肥后体重回升非常有效， 而对于减肥，激素和神经介质影响着复杂和高度的 运动相关的食欲和食物摄入量的变化以及运动相关的影响 能量消耗和运动耐力等相关生理学知识知之甚少。在当前 我们的目标是研究激素ghrelin及其受体生长激素的作用。 促分泌素受体(GHSR)在调节运动对摄食量的影响中的作用 锻炼耐力。该提案是对最近在老鼠身上发表的研究结果的跟进，该发现表明 运动会短暂地提高血液中生长激素的水平，而在没有这种作用的情况下会增加。 Ghrelin、运动后食物摄入量和运动耐力都明显降低。该提案使用了 独一无二的转基因小鼠模型研究运动调节机制-- Ghrelin及其受体诱导的Ghrelin释放和神经元部位及其他机制 受体介导对运动和运动耐力的代谢反应。特别是，我们将确定是否 Ghrelin依赖或Ghrelin非依赖(构成)的信号是代谢所必需的。 通过评估ghrelin缺失和GHSR突变(消除 对食物摄入量、能量消耗、神经元兴奋性和运动耐力的影响。 我们将使用Ghrelin细胞中缺乏β1肾上腺素能受体的小鼠模型来确定 这些Ghrelin细胞β1-肾上腺素能受体的激活是由交感-肾上腺系统引起的。 胃促生长素对运动的反应。我们还将选择性地使用弓形体内缺乏GHSR的小鼠 下丘脑AgRP神经元或下丘脑腹内侧部SF1神经元与化学遗传学- 抑制下丘脑内侧基底区GHSR表达的神经元以确定这些群体是否 下丘脑神经元介导Ghrelin系统对代谢和运动相关的影响 锻炼耐力。我们的研究将对运动的新陈代谢影响提供基本的见解， 运动耐力、弓状下丘脑AgRP和POMC神经元兴奋性、Ghrelin细胞生理学和 Ghrelin行动。最终，我们希望研究Ghrelin系统在代谢反应中的作用 运动可能会让我们确定并在治疗上利用运动促进的机制 全身健康。