Targeting hypothalamic steroid receptor co-activator-1 to treat obesity

靶向下丘脑类固醇受体辅激活剂-1 治疗肥胖

• 批准号: 8921991
• 负责人: YONG XU
• 金额: $ 31.21万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8921991
• 关键词: Address; Anorexia; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Cardiovascular Diseases; Cells; Chemicals; Clinical Trials; Comorbidity; Complex; Cues; Data; Development; Diet; Dissociation; Dose; Equilibrium; Fatty acid glycerol esters; Functional disorder; Gene Expression; Gene Targeting; Genetic; Genetic Transcription; Goals; Health; Homeostasis; Human; Hypothalamic dysfunction; Hypothalamic structure; In Vitro; Injection of therapeutic agent; Intervention; Lead; Leptin; Mediating; Metabolic; Modeling; Molecular; Molecular Mechanisms of Action; Molecular Target; Mus; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nuclear Receptors; Obesity; Physiological; Pilot Projects; Play; Predisposition; Prevalence; Pro-Opiomelanocortin; Protein Family; Regulation; Risk Factors; Rodent; Role; SF1; Series; Signaling Molecule; Stat3 protein; Steroid Receptors; Testing; Weight Gain; combat; design; drug candidate; effective therapy; efficacy testing; feeding; global health; in vivo; mouse model; novel; obesity prevention; obesity treatment; overexpression; prevent; research study; response; transcription factor; ventromedial hypothalamic nucleus

DESCRIPTION (provided by applicant): Obesity is a major risk factor for type II diabetes and cardiovascular disease. Increased understanding of body weight regulation may lead to effective strategies to combat obesity. Hypothalamic neurons, including pro-opiomelanocortin (POMC) neurons and steroidogenic factor-1 (SF1) neurons, integrate multiple metabolic cues to provide a coordinated control of energy homeostasis. In our pilot studies, we found that a nuclear receptor co-activator, namely steroid receptor co-activator-1 (SRC1), is expressed in majority of POMC and SF1 neurons. We observed that hypothalamic SRC1 interacts with pSTAT3 and SF1. In particular, the hypothalamic SRC1-pSTAT3 interaction can be enhanced by leptin, but is disrupted in mice with diet-induced obesity (DIO). Importantly, we observed the similar SRC1-pSTAT3 dissociation in the hypothalami from obese humans. These raise the hypotheses that (1) SRC1 in POMC and/or SF1 neurons mediate leptin actions through its interactions with pSTAT3 or SF1; (2) the dysfunction of hypothalamic SRC1 contributes to the development of DIO; (3) interventions enhancing hypothalamic SRC1 functions interaction can be used to prevent or treat obesity. Consistent with this, we found that SRC1lox/lox/POMC-Cre mice, which lack SRC1 in both mature and developing POMC neurons, are less sensitive to leptin-induced anorexia and more susceptible to DIO. Importantly, we identified a small chemical that enhances the hypothalamic SRC1-pSTAT3 interaction and partially prevents DIO. Objectives of the current application are to generate mice lacking or overexpressing SRC1 only in mature POMC neurons (Aim 1) or SF1 neurons (Aim 2), and systemically examine the effects of such deletion/overexpression on energy homeostasis and leptin sensitivity. In addition, a series of in vivo and in vitro experiments are designed to explore the molecular mechanisms by which hypothalamic SRC1 interacts with pSTAT3 and SF1, and regulates their transcriptional activities. Finally, we will continue to test the anti-obesity efficacy of the small chemical in a number of rodent obese models and to explore molecular mechanisms and action targets of the chemical. Thus, these experiments may reveal novel mechanisms underlying the development of obesity, identify hypothalamic SRC1 as a rational target for the treatment of obesity, and lead to discovery of an obesity drug candidate suitable for clinical trials.

描述（由申请人提供）：肥胖是 II 型糖尿病和心血管疾病的主要危险因素。增加对体重调节的了解可能会导致对抗肥胖的有效策略。下丘脑神经元，包括阿片黑皮质素原 (POMC) 神经元和类固醇生成因子 1 (SF1) 神经元，整合多种代谢线索以提供能量稳态的协调控制。在我们的初步研究中，我们发现核受体辅激活剂，即类固醇受体辅激活剂-1 (SRC1)，在大多数 POMC 和 SF1 神经元中表达。我们观察到下丘脑 SRC1 与 pSTAT3 和 SF1 相互作用。特别是，瘦素可以增强下丘脑 SRC1-pSTAT3 相互作用，但在饮食诱导肥胖 (DIO) 的小鼠中会受到破坏。重要的是，我们在肥胖人群的下丘脑中观察到类似的 SRC1-pSTAT3 解离。这些提出了以下假设：(1) POMC 和/或 SF1 神经元中的 SRC1 通过与 pSTAT3 或 SF1 相互作用介导瘦素作用； (2)下丘脑SRC1功能障碍有助于DIO的发生； (3)增强下丘脑SRC1功能相互作用的干预措施可用于预防或治疗肥胖。与此一致的是，我们发现 SRC1lox/lox/POMC-Cre 小鼠在成熟和发育中的 POMC 神经元中都缺乏 SRC1，对瘦素诱导的厌食症不太敏感，并且更容易受到 DIO 的影响。重要的是，我们发现了一种小化学物质，可以增强下丘脑 SRC1-pSTAT3 相互作用并部分预防 DIO。当前应用的目标是产生仅在成熟 POMC 神经元（目标 1）或 SF1 神经元（目标 2）中缺乏或过度表达 SRC1 的小鼠，并系统地检查这种缺失/过度表达对能量稳态和瘦素敏感性的影响。此外，还设计了一系列体内外实验来探讨下丘脑SRC1与pSTAT3和SF1相互作用并调节其转录活性的分子机制。最后，我们将继续在多个啮齿动物肥胖模型中测试该小化学物质的抗肥胖功效，并探索该化学物质的分子机制和作用靶点。因此，这些实验可能揭示肥胖发展的新机制，确定下丘脑SRC1作为治疗肥胖的合理靶点，并导致发现适合临床试验的肥胖候选药物。