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

项目摘要 运动通常对预防体重增加、预防体重减轻后体重反弹非常有效， 然而，对于减肥，影响复杂和高度复杂的激素和神经介质， 不同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 能量消耗和相关生理学如运动耐力知之甚少。在当前 建议，我们的目标是调查激素ghrelin及其受体，生长激素的作用 促分泌素受体（GHSR），介导运动对食物摄入的影响，以及介导 锻炼耐力。该提案是对最近发表的小鼠研究结果的跟进，这些研究结果表明， 运动短暂地提高循环水平的激素ghrelin和没有行动，这增加 胃饥饿素、运动后食物摄入和运动耐力都显著降低。该提案使用一个 独特的基因工程小鼠模型集合，用于研究调节运动的机制- 诱导的生长素释放和神经元位点以及生长素及其 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， 生长激素释放肽依赖性或生长激素释放肽非依赖性（组成性）信号传导通过GHSR是代谢所需的。 通过评估生长激素释放肽缺失和GHSR突变（消除了 GHSR组成活性）对食物摄入、能量消耗、神经元兴奋性和运动耐力的影响。 我们将使用一个缺乏β1-肾上腺素能受体的小鼠模型，专门在生长激素释放肽细胞，以确定是否 这些生长激素释放肽细胞β1-肾上腺素能受体的激活是必需的，如交感肾上腺系统所诱导的 对运动的反应。我们还将使用缺乏GHSR的小鼠， 下丘脑AgRP神经元或下丘脑腹内侧SF 1神经元和具有化学发生学- 抑制中基底下丘脑GHSR表达神经元，以确定这些群体是否 下丘脑神经元介导生长素释放肽系统对代谢的运动相关作用， 锻炼耐力。我们的研究将为运动对代谢的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 饥饿激素作用。最终，我们希望研究生长激素释放肽系统在代谢反应中的作用， 运动可以让我们确定和治疗利用的机制，运动促进 全身健康。

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.