Sex Differences in the Cannabioid Regulation of Energy Homeostasis

大麻素能量稳态调节的性别差异

• 批准号: 8986614
• 负责人: EDWARD J WAGNER
• 金额: $ 10万
• 依托单位: WESTERN UNIVERSITY OF HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8986614
• 关键词: 2-arachidonylglycerol; AIDS related cancer; Acute; Address; Affect; Agonist; Androgens; Animal Model; Anxiety; Appetite Regulation; Attenuated; Awareness; Behavioral; Biological; Biological Process; Body Temperature; CNR1 gene; Cannabinoids; Carbon Dioxide; Cavia; Consumption; Coupled; Desire for food; Development; Diet; Eating; Endocannabinoids; Energy Intake; Energy Metabolism; Enzymes; Equilibrium; Estradiol; Estrogen Receptors; Estrogens; Female; Gender; Glutamates; Goals; Gonadal Steroid Hormones; Homeostasis; Hormonal; Hyperphagia; Hypothalamic structure; Intoxication; Learning; Ligands; Membrane; Memory; Metabolic; Metabolism; Molecular; National Institute of Drug Abuse; Neurons; Nitric Oxide Synthase; Obesity; Pain management; Pathway interactions; Pattern; Phosphatidylinositols; Phosphotransferases; Physiological; Physiological Processes; Pro-Opiomelanocortin; Production; Protein Kinase C; Receptor Signaling; Regulation; Reproduction; Research; Sex Characteristics; Shapes; Stress; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic Transmission; Techniques; Testing; Testosterone; Thermogenesis; Woman; Women' s Health; adenylate kinase; anandamide; balance testing; drug of abuse; energy balance; feeding; improved; increased appetite; interdisciplinary approach; male; men; natural hypothermia; neurotransmission; postsynaptic; presynaptic; public health relevance; receptor; sex; steroid hormone; therapeutic effectiveness; wasting

DESCRIPTION (provided by applicant): Cannabinoids 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 appetite, core body temperature, metabolism, and the cellular mechanism(s) by which they affect the excitability of proopiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus to alter these actions. The fundamental hypothesis is that cannabinoids modulate energy balance in a sex-dependent fashion that can be differentially influenced by gonadal steroid hormones. They do so by 1) presynaptically altering the balance between excitatory + and inhibitory neurotransmission and 2) augmenting postsynaptic K currents, thereby reducing POMC neuronal activity in a manner that is sexually differentiated and dependent on the gonadal steroid milieu. Cannabinoid regulation of energy homeostasis and synaptic transmission onto appetite-suppressing POMC neurons will be studied using a guinea pig animal model. Females are ovariectomized and males orchidectomized one week prior to experimentation, respectively. In Specific Aim 1, I will evaluate the mechanisms through which androgens and estrogens differentially modulate the cannabinoid regulation of energy balance by assessing how they influence 1) the capability of CB1 receptor agonists and antagonists to alter food intake, meal pattern, core body temperature, O2 consumption, CO2 and metabolic heat production, 2) endogenous cannabinoid production and subsequent presynaptic inhibition of excitatory glutamatergic and inhibitory GABAergic synaptic input onto POMC neurons, and 3) the activity and expression of critical energy-sensing enzymes, under different dietary and motivational conditions. In Specific Aim 2, the objective is to determine the receptor subtype(s) through which estrogens attenuate the cannabinoid modulation of energy balance. Specifically, I will evaluate whether agonists for the Gq-coupled membrane estrogen receptor m(ER), ER¿, ER¿ and/or GPR30 diminish cannabinoid-induced changes in energy intake and expenditure, as well the presynaptic inhibition of glutamatergic input onto POMC neurons. This proposal describes an integrated approach to study sex differences in, and gonadal steroid hormonal on, the cannabinoid regulation of energy balance, and will elucidate the relevant cellular mechanisms that predetermine the sensitivity of males and females to the acute perturbation of energy intake and expenditure very early in cannabinoid abuse.

描述（由申请人提供）：大麻素对生殖和能量稳态等生物过程的下丘脑控制产生深远影响。该提案的总体目标是更好地了解大麻素对食欲，核心体温，代谢的调节，以及它们影响下丘脑弓状核中阿黑皮素原（POMC）神经元兴奋性以改变这些行为的细胞机制。基本假设是大麻素以性别依赖的方式调节能量平衡，这种方式可以受到性腺类固醇激素的不同影响。它们通过1）突触前改变兴奋性+和抑制性神经传递之间的平衡和2）增加突触后K电流，从而以性分化和依赖于性腺类固醇环境的方式降低POMC神经元活性。将使用豚鼠动物模型研究大麻素对食欲抑制POMC神经元的能量稳态和突触传递的调节。分别在实验前一周切除雌性动物的卵巢和切除雄性动物的卵巢。在具体目标1中，我将通过评估雄激素和雌激素如何影响1）CB 1受体激动剂和拮抗剂改变食物摄入、膳食模式、核心体温、O2消耗、CO2和代谢产热的能力，2）内源性大麻素的产生和随后对POMC神经元上的兴奋性多巴胺能和抑制性GABA能突触输入的突触前抑制，和3）关键能量感应酶的活性和表达，在不同的饮食和动机条件下。在具体目标2中，目的是确定受体亚型，雌激素通过该受体亚型减弱能量平衡的大麻素调节。具体来说，我将评估Gq偶联膜雌激素受体m（ER），ER <$，ER <$和/或GPR 30的激动剂是否减少大麻素诱导的能量摄入和消耗的变化，以及对POMC神经元的突触前抑制。该提案描述了一个综合的方法来研究性别差异，和性腺类固醇激素，能量平衡的大麻素调节，并将阐明相关的细胞机制，预先确定的敏感性的男性和女性的能量摄入量和支出的急性扰动非常早期的大麻素滥用。