Feeding Driven by POMC Neurons

POMC 神经元驱动的进食

• 批准号: 9325239
• 负责人: TAMAS L HORVATH
• 金额: $ 50.1万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-15 至 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9325239
• 关键词: Acute; Affect; Agonist; Animals; Appetite Stimulants; Binding; Biochemical; Biological; Brain; CB1 knockout; CNR1 gene; Cannabinoids; Cell membrane; Cells; Data; Diet; Disease; Elements; Endocannabinoids; Endorphins; Energy Metabolism; Fasting; Feeding behaviors; Food deprivation (experimental); Glucose; Goals; High Fat Diet; Hypothalamic structure; Impairment; Knock-out; Knockout Mice; Mediating; Metabolism; Mitochondria; Molecular; Mus; Neurobiology; Neurons; Obese Mice; Obesity; Opioid Receptor; Permeability; Phase; Physiological; Physiology; Play; Receptor Activation; Regulation; Role; Structure of nucleus infundibularis hypothalami; System; Testing; Transgenic Mice; UCP2 protein; Yin-Yang; behavioral response; beta-Endorphin; feeding; knock-down; knockout animal; novel; presynaptic; receptor; response; selective expression; vesicular release

Over the past 20 years, the arcuate nucleus melanocortin system emerged as a crucial regulator of feeding and energy metabolism. A yin-yang relationship between orexigenic AgRP and anorexigenic POMC neurons has been considered a primum movens in control of whole body metabolism. Strikingly, however, we recently discovered that activation of POMC neurons by cannabinoid receptor 1 (CB1R) is associated with increased feeding, and, that POMC neuronal activation is crucial for cannabinoid-induced feeding. Our observations suggest that the orexigenic tone of POMC neurons rely on switching vesicular release of -MSH to - endorphin. Indeed, inhibition of opiate receptors in the brain diminished cannabinoid-induced feeding. We also found that CB1R activation-induced feeding is associated whit uncoupling protein 2 (UCP2)-dependent mitochondrial dynamics in the hypothalamus, of which selective impairment by knocking down UCP2 abolished CB1R-induced feeding. These observations gave impetus to the hypothesis that cell autonomous expression of CB1R and UCP2 in POMC neurons are critical for CB1R-induced feeding and that this behavioral response relies on POMC-released -endorphin. We also predict that POMC-driven feeding occurs in physiological circumstances. For example, elevated endogenous cannabinoid levels coincide with activation of POMC neurons after feeding initiation subsequent to a prolonged fast as well as in diet-induced obese mice. We hypothesize that an orexigenic POMC tone, utilizing the mechanisms described above, is an important element in rebound feeding after food deprivation and in high fat diet-induced obesity. We will test our hypotheses by utilization of unique transgenic mice lines in combination with state-of- the art neurobiological, cellular biological, biochemical and physiological approaches. With the execution of these studies, we will deliver an entirely novel aspect of feeding regulation by the POMC system with immediate implications to physiology and disease states of metabolism.

在过去的 20 年里，弓状核黑皮质素系统成为进食的重要调节因子。 和能量代谢。食欲AgRP与厌食POMC神经元之间的阴阳关系 被认为是控制全身新陈代谢的主要动作。然而，引人注目的是，我们最近 发现大麻素受体 1 (CB1R) 激活 POMC 神经元与增加 POMC 神经元激活对于大麻素诱导的进食至关重要。我们的观察 表明 POMC 神经元的食欲诱发音依赖于将 α-MSH 的囊泡释放转换为 α- 内啡肽。事实上，抑制大脑中的阿片受体可以减少大麻素引起的进食。我们也 发现 CB1R 激活诱导的进食与解偶联蛋白 2 (UCP2) 依赖性相关 下丘脑线粒体动力学，通过敲除 UCP2 消除选择性损伤 CB1R诱导喂养。这些观察结果推动了细胞自主的假设 POMC 神经元中 CB1R 和 UCP2 的表达对于 CB1R 诱导的进食至关重要，并且这 行为反应依赖于 POMC 释放的 -内啡肽。我们还预测 POMC 驱动的喂食 发生在生理情况下。例如，内源性大麻素水平升高与 长时间禁食后以及饮食诱导的进食开始后 POMC 神经元的激活 肥胖的老鼠。我们假设，利用上述机制，产生食欲的 POMC 音调， 是食物剥夺后反弹喂养和高脂肪饮食引起的肥胖的一个重要因素。 我们将通过利用独特的转基因小鼠品系结合现状来检验我们的假设 最先进的神经生物学、细胞生物学、生物化学和生理学方法。随着执行 在这些研究中，我们将通过 POMC 系统提供一个全新的喂养调节方面 对新陈代谢的生理学和疾病状态有直接影响。