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

基本信息

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
项目类别：
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

项目摘要

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。对体重调节的了解增加可能导致有效的策略来打击肥胖症。下丘脑神经元，包括促蛋白酶素（POMC）神经元和类固醇生成因子-1（SF1）神经元，整合了多种代谢线索，以提供对能量稳态的协调控制。在我们的试点研究中，我们发现核受体共激活剂，即类固醇受体共激活剂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，下丘脑SRC1-PSTAT3相互作用可以通过瘦素增强，但在饮食诱导的肥胖症（DIO）的小鼠中被破坏。重要的是，我们观察到了肥胖人类下丘脑中类似的SRC1-PSTAT3解离。这些提出的假设是（1）pOMC和/或SF1神经元中的SRC1通过与PSTAT3或SF1的相互作用介导瘦素作用；（2）下丘脑SRC1的功能障碍有助于DIO的发展；（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症。与此相一致，我们发现Src1lox/lox/pomc-cre小鼠在成熟和发育中缺乏src1的POMC神经元对瘦素诱导的厌食症的敏感程度较低，并且对DIO更容易受到敏感。重要的是，我们确定了一种小型化学物质，可增强下丘脑SRC1-PSTAT3相互作用并部分防止DIO。当前应用的目的是仅在成熟的POMC神经元（AIM 1）或SF1神经元（AIM 2）中生成缺乏或过表达SRC1的小鼠，并系统地检查这种缺失/过表达对能量稳态和瘦素敏感性的影响。此外，一系列体内和体外实验旨在探索下丘脑SRC1与PSTAT3和SF1相互作用的分子机制，并调节其转录活性。最后，我们将继续在许多啮齿动物肥胖模型中测试小化学物质的抗肥胖功效，并探索化学物质的分子机制和作用靶标。因此，这些实验可能揭示了肥胖发展的基本机制，将下丘脑SRC1确定为治疗肥胖症的合理靶标，并导致发现适合临床试验的肥胖药物候选药物。