Hypothalamic mechanisms mediating estrogenic regulation of energy homeostasis

下丘脑机制介导能量稳态的雌激素调节

• 批准号: 8323385
• 负责人: YONG XU
• 金额: $ 24.65万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-20 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323385
• 关键词: 1-Phosphatidylinositol 3-Kinase; Adverse effects; Alleles; Animal Model; Animals; Arts; Attenuated; Body Weight; Brain; Catalytic Domain; Cell Nucleus; Cessation of life; Coronary heart disease; Data; Development; Diabetes Mellitus; Disease; Eating; Energy Intake; Energy Metabolism; Estradiol; Estrogen Receptors; Estrogen Replacements; Estrogen Therapy; Estrogens; Event; Female; Food Energy; Genomics; Gonadal Steroid Hormones; Health; Heart Diseases; Homeostasis; Hormone replacement therapy; Hypertension; Hypothalamic structure; Incidence; Individual; Intake; Lead; Malignant Neoplasms; Mediating; Menopause; Mentors; Metabolic; Metabolic syndrome; Mus; Neurons; Neurotransmitters; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Ovarian; Overweight; Pathway interactions; Peripheral; Phase; Phenotype; Physiological; Play; Population; Pro-Opiomelanocortin; Protein Isoforms; Receptor Signaling; Regulation; Risk; Role; SF1; Signal Transduction; Site; Steroids; Stroke; Structure of nucleus infundibularis hypothalami; Technology; Testing; Tissues; Transgenes; United States; Weight Gain; Woman; brain cell; combat; energy balance; global health; kinase inhibitor; malignant breast neoplasm; mouse model; non-genomic; novel; novel therapeutics; premature; receptor; recombinase; small hairpin RNA

DESCRIPTION (provided by applicant): The increasing incidence of obesity is a major health issue facing the world and increased understanding of body weight regulation may lead to effective strategies to combat obesity and related disorders, such as diabetes. The sex hormone, estrogen, plays a beneficial role in maintaining normal body weight as women show dramatically increased risks for developing obesity and diabetes when they enter menopause. Hormone replacement therapy may be a way to reduce these risks, but actions of estrogen via its receptors in the peripheral tissues cause unwanted effects, such as cancer and heart diseases. Thus, one objective of the proposed study is to determine whether the anti-obesity effects of estrogen are mediated by one estrogen receptor isoform, ER(, expressed by specific populations of brain cells, namely POMC neurons and SF1 neurons. To this end, we will generate mouse models with ER( deleted selectively in POMC neurons and/or SF1 neurons, and assess whether the metabolic benefits induced by estrogen are abrogated in these animals. We will also generate mice whose POMC or SF1 neurons lack activity of PI3 kinase, which is an intracellular molecule activated by estrogen. By assessing effects of estrogen in these mice, we will determine if the PI3 kinase is required for estrogenic actions on energy balance. Thus, the proposed study will not only advance our understanding about the mechanisms by which sex hormone regulates brain functions to provide a coordinated regulation of body weight, but also help identify rationale targets for developing more specific estrogen therapies that provide metabolic benefits with no or fewer side effects.

描述（由申请人提供）： 肥胖的发生率的增加是世界面临的主要健康问题，对体重调节的了解可能会导致有效的策略来打击肥胖和相关疾病，例如糖尿病。性激素，雌激素在保持正常体重方面起着有益的作用，因为女性在进入更年期时表现出大大增加了肥胖和糖尿病的风险。激素替代疗法可能是降低这些风险的一种方法，但是雌激素通过其受体在周围组织中的作用会引起不良影响，例如癌症和心脏病。因此，拟议研究的一个目的是确定雌激素的抗肥胖作用是否是由一个雌激素受体同工型ER介导的（由脑细胞的特定群体表达，即POMC神经元和SF1神经元。为此，我们将生成具有ER的小鼠模型（在POMC神经元和/或SF1神经元中有选择性删除，并评估这些动物中雌激素诱导的代谢益处是否被废除。我们还将产生POMC或SF1神经元缺乏PI3激酶的小鼠，而PI3激酶的活性，这是PI3激酶的活性。是通过评估雌激素在这些小鼠中的作用来激活的细胞内分子，我们将确定雌激酶是否需要雌激酶对能量平衡的作用。激素调节大脑功能以提供体重的协调调节，但也有助于确定开发更具体的雌激素疗法的基本原理，这些疗法提供了代谢益处，没有或更少的副作用。

项目成果

Adrenomedullin in the rostral ventrolateral medulla increases arterial pressure and heart rate: roles of glutamate and nitric oxide.

延髓头端腹外侧的肾上腺髓质素增加动脉压和心率：谷氨酸和一氧化氮的作用。

• DOI: 10.1152/ajpregu.00188.2004
• 发表时间: 2004
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: Xu,Yong;Krukoff,TeresaL
• 通讯作者: Krukoff,TeresaL