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

描述(申请人提供)：肥胖是二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，包括阿片黑素皮质素原(POMC)神经元和类固醇生成因子-1(SF1)神经元，整合多种代谢信号，提供能量稳态的协调控制。在我们的前期研究中，我们发现核受体共激活物，即类固醇受体共激活物-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的相互作用，但在饮食诱导肥胖(DIO)的小鼠中却被破坏。重要的是，我们在肥胖者的下丘脑中观察到了类似的SRC1-pSTAT3解离。这就提出了假设：(1)POMC和/或SF1神经元中的SRC1通过与pSTAT3或SF1的相互作用来介导瘦素的作用；(2)下丘脑SRC1的功能障碍有助于DIO的发生；(3)加强下丘脑SRC1功能相互作用的干预可用于预防或治疗肥胖。与此一致，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，对瘦素诱导的厌食不那么敏感，对DIO更敏感。重要的是，我们确定了一种小的化学物质，它可以增强下丘脑SRC1-pSTAT3的相互作用，并部分防止DIO。目前应用的目的是建立仅在成熟的POMC神经元(目标1)或SF1神经元(目标2)缺乏或过度表达SRC1的小鼠，并系统地检测这种缺失/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和体外实验，以探索下丘脑SRC1与pSTAT3和SF1相互作用的分子机制，并调节它们的转录活性。最后，我们将继续在多个啮齿动物肥胖模型上测试该小化学物质的减肥效果，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生的新机制，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减肥药候选药物。

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.