Sex Differences in the Cannabinoid Regulation of Energy Homeostasis.

大麻素能量稳态调节的性别差异。

• 批准号: 9302013
• 负责人: EDWARD J WAGNER
• 金额: $ 40.11万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2020-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9302013
• 关键词: 1-Phosphatidylinositol 3-Kinase; 5' -AMP-activated protein kinase; Acquired Immunodeficiency Syndrome; Address; Affect; Androgens; Animal Model; Animals; Anxiety; Attenuated; Awareness; Behavioral; Biological Process; Brain; Brain region; CNR1 gene; Cannabinoids; Cell Nucleus; Chemicals; Communication; Coupled; Desire for food; Development; Diabetes Mellitus; Diet; Drug Addiction; Electrophysiology (science); Elements; Endocannabinoids; Energy Intake; Energy Metabolism; Enterobacteria phage P1 Cre recombinase; Enzymes; Estradiol; Estrogens; Excision; Exposure to; Female; Gender; Genes; Glutamates; Goals; Gonadal Steroid Hormones; Gonadal structure; High Fat Diet; Homeostasis; Hormonal; Hypothalamic structure; Impairment; In Vitro; Insulin Resistance; Intoxication; Learning; Light; Link; Malignant Neoplasms; Mediating; Memory; Metabolism; Muscarinic M3 Receptor; National Institute of Drug Abuse; Nerve; Neurons; Nitric Oxide; Obesity; Pain management; Pharmacology; Phosphatidylinositols; Pro-Opiomelanocortin; Protein Kinase; Protocols documentation; Regulation; Reproduction; Research; Rodent; SF1; Satiation; Sex Characteristics; Shapes; Signal Transduction; Signal Transduction Pathway; Signaling Molecule; Site; Stress; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic Cleft; Synaptic Transmission; System; Techniques; Testing; Testosterone; Transgenic Organisms; Translating; Variant; Viral; Viral Vector; Western Blotting; Woman; Women' s Health; drug of abuse; endocannabinoid signaling; energy balance; enzyme activity; estrogenic; exogenous cannabinoid; feeding; food addiction; food consumption; gender difference; improved; in vivo; increased appetite; male; men; neurotransmission; optogenetics; promoter; receptor-mediated signaling; reuptake; sex; steroid hormone; therapeutic effectiveness; tripolyphosphate; ventromedial hypothalamic nucleus; wasting

Project Summary: Cannabinoids, both endogenous and exogenous, exert a profound impact on the hypothalamic control of biological processes such as reproduction and energy homeostasis. The overall goal of this proposal is to gain a better understanding of the cannabinoid regulation of energy homeostasis, and the cellular mechanism(s) by which they affect the excitability of anorexigenic proopiomelanocortin (POMC) neurons in the arcuate nucleus (ARC) of the hypothalamus to alter these actions. The fundamental hypothesis is that endocannabinoids modulate energy balance in a sex- and diet-dependent fashion that can be differentially influenced by gonadal steroid hormones. They do so, in large part, via retrograde inhibition of excitatory glutamatergic neurotransmission in POMC neurons in a manner that is sexually differentiated, and dependent on dietary composition and the gonadal steroid milieu. Endocannabinoid regulation of energy homeostasis and synaptic transmission onto POMC neurons will be studied using a transgenic, Nr5a1-cre animal model, in which either channelrhodpsin-2 or a modified Gq-coupled muscarinic M3 receptor is delivered via a viral vector construct into the hypothalamic ventromedial nucleus (VMN) and integrated into neurons expressing steroidogenic factor- 1 (SF-1; encoded by the Nr5a1 gene) for in vivo and in vitro optogenetic experimentation. Females are ovariectomized and males orchidectomized one week prior to experimentation, respectively, and treated with estradiol, testosterone, or their respective vehicles according to well-established protocols. In Specific Aim 1, I will evaluate the mechanisms through which long-term exposure to a "Westernized" high-fat diet differentially enhances endocannabinoid sensitivity in males and females by assessing how it influences the capability of endogenous cannabinoids to retrogradely inhibit light- and chemically- evoked glutamatergic neurotransmission at VMN SF-1/ARC POMC synapses. In Specific Aim 2, the objective is to determine whether these high-fat diet-induced alterations in endocannabinoid sensitivity effectively translate into changes in energy balance. Specifically, I will evaluate whether high-fat diet exposure differentially attenuates the capability of opto- and chemogenetically stimulated VMN SF-1 neurons to suppress energy intake and enhance energy expenditure, and whether these adaptations are due to alterations in the expression/activity of the energy-sensing signaling molecules like phosphatidylinositol-3-kinase and AMP-activated protein kinase. This proposal describes an integrated approach to study sex differences in, and gonadal steroid hormonal influences on, the cannabinoid regulation of energy balance. Further, it will elucidate the relevant cellular mechanisms and neuroanatomical substrates that differentially predispose males and females to dysregulated endocannabinoid signaling and food consumption under conditions of diet-induced obesity/insulin resistance.

项目摘要：内源性和外源性大麻素对人类的健康产生深远影响。 下丘脑控制生物过程，如生殖和能量平衡。整体 该提案的目的是更好地了解大麻素对能量的调节 稳态，以及它们影响促肾上腺皮质激素分泌的兴奋性的细胞机制。 前阿黑皮素（POMC）神经元在弓状核（ARC）的下丘脑，以改变这些 行动基本假设是内源性大麻素调节性和性的能量平衡。 饮食依赖的方式，可以通过性腺类固醇激素的差异影响。他们这样做，在 在很大程度上，通过逆行抑制POMC神经元的兴奋性多巴胺能神经传递， 性分化的方式，依赖于饮食成分和性腺类固醇 环境。内源性大麻素对POMC能量稳态和突触传递的调节 将使用转基因的Nr 5a 1-cre动物模型研究神经元，其中通道视紫红质-2 或经修饰的Gq偶联的毒蕈碱M3受体通过病毒载体构建体递送到所述细胞中。 下丘脑腹内侧核（VMN）和整合到神经元表达类固醇生成因子- 1（SF-1;由Nr 5a 1基因编码）用于体内和体外光遗传学实验。女性 分别在实验前一周切除卵巢和切除卵巢的雄性动物， 与雌二醇、睾酮或它们各自的载体根据良好建立的方案进行。在 具体目标1，我将评估长期接触“西化”的机制， 高脂饮食通过评估如何差异增强男性和女性的内源性大麻素敏感性 它会影响内源性大麻素的能力，以逆行抑制光-和化学- 在VMN SF-1/ARC POMC突触处诱发的突触能神经传递。具体目标2 目的是确定这些高脂肪饮食是否诱导内源性大麻素敏感性的改变， 有效地转化为能量平衡的变化。具体来说，我将评估高脂肪饮食是否 暴露差异性地减弱光刺激和化学发生刺激的VMN SF-1的能力 神经元抑制能量摄入和增加能量消耗，以及这些适应是否 由于能量感应信号分子的表达/活性的改变， 磷脂酰肌醇-3-激酶和AMP活化蛋白激酶。该提案描述了一个综合的 研究大麻素的性别差异和性腺类固醇激素影响的方法 调节能量平衡。此外，它将阐明相关的细胞机制， 不同的神经解剖学基质使男性和女性的失调 在饮食诱导的肥胖/胰岛素条件下内源性大麻素信号传导和食物消耗 阻力