Hypothalamic SIRT1 and Energy Balance

下丘脑 SIRT1 和能量平衡

• 批准号: 8508411
• 负责人: EDUARDO A. NILLNI
• 金额: $ 6.68万
• 依托单位: RHODE ISLAND HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8508411
• 关键词: 5' -AMP-activated protein kinase; Accounting; Acetylation; Adult; Affect; Aging; American; Anti-Obesity Agents; Apoptosis; Appetite Depressants; Behavioral; Biological Process; Body Weight; Body Weight decreased; Cardiovascular Diseases; Cells; Cessation of life; Consumption; Country; Data; Deacetylase; Deacetylation; Dependence; Desire for food; Developed Countries; Development; Diet; Dyslipidemias; Eating; Energy Intake; Energy Metabolism; Enzymes; Epidemic; Exposure to; Fasting; Fatty acid glycerol esters; Generations; Genetic; Health; Homeostasis; Hormonal; Hormones; Human; Hypothalamic structure; In Vitro; Journals; Leptin; Link; Malignant Neoplasms; Mediating; Medical Research; Melanocyte stimulating hormone; Metabolic; Metabolism; Molecular; Mus; Nervous system structure; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutritional status; Obesity; Overweight; Oxidation-Reduction; Pathogenesis; Pathway interactions; Peptides; Peripheral; Plasma; Play; Prevalence; Pro-Opiomelanocortin; Proprotein Convertase 1; Proprotein Convertase 2; Publishing; Rattus; Regulation; Research; Resistance; Rodent; Role; SHU 9119; Sense Organs; Severities; Signal Transduction; Small Interfering RNA; Staging; Structure of nucleus infundibularis hypothalami; Surveys; Testing; Tissues; United States; Weight Gain; World Health Organization; base; effective therapy; energy balance; expectation; forkhead protein; in vivo; knock-down; mTOR protein; medical complication; neural circuit; neuropeptide Y; novel; obesity treatment; peptide hormone; response; sensor; treatment strategy

DESCRIPTION (provided by applicant): Obesity and its associated medical complications including type II diabetes, cardiovascular disease, dyslipidemia, and cancer account for more than 300,000 deaths per year in the United States. Obesity treatment strategies often do not result in adequate sustained weight loss, and the prevalence and severity of obesity in the U.S. and many other countries is progressively increasing. Recent surveys classify roughly 1/3 of all Americans as obese. The complexity of the obesity condition results from the interaction between environmental and predisposed genetic factors. A more thorough understanding of the molecular mechanisms underlying the pathogenesis of obesity and regulation of energy metabolism is essential for the development of effective therapies. Energy homeostasis is maintained by tissues and organs that sense and respond to the nutritional status of the body. At the central level, the hypothalamus is the primary component of the nervous system in interpreting adiposity or nutrient related inputs; it delivers hormonal and behavioral responses with the ultimate purpose of regulating energy intake and consumption. At the molecular level, enzymes called nutrient or energy sensors mimic the role of the tissues involved in energy balance. Two key energy/nutrient sensors, mTOR (mammalian target of rapamycin) and AMPK (AMP activated kinase) - in addition to their extensive metabolic roles in the peripheral tissues - are involved in the control of food intake in the hypothalamus. The enzyme Sirt1 is an evolutionarily conserved NAD+-dependent deacetylase involved in many biological processes including cellular differentiation, apoptosis, metabolism, and aging. Because of its dependence on NAD+, Sirt1 also functions as a nutrient/redox sensor. Thus, we hypothesized that Sirt1 could play a role in the control of energy balance, perhaps by influencing the mTOR or AMPK pathways, at the level of the hypothalamus. Our preliminary results indicate that pharmacological inhibition of hypothalamic Sirt1 or siRNA mediated knock down of Sirt1 in the arcuate nucleus (ARC) of the hypothalamus decreases food intake and body weight gain. Therefore, this proposal provides a novel view assigned to Sirt1 as a cellular energy sensor regulating energy balance at the hypothalamic level. Sirt1 links nutrient availability to energy homeostasis at the hypothalamic level, and this effect depends -at least in part- on the fasting induced and Sirt1 mediated regulation of FoxO1 deacetylation and mTOR signaling. Based on these findings we will: Aim 1: Determine the targets and mechanism of action hypothalamic Sirt1 signaling regulating energy balance. To this purpose we will determine whether: 1. Sirt1 regulates the anorexigenic POMC as well as the orexigenic Agouti-related peptide (AgRP) and neuropeptide Y (NPY) through FoxO1 in a nutrient dependent manner. 2. Sirt1 deacetylates and inhibits Stat3 in a nutrient sensitive manner 3. Sirt1 represses mTOR signaling at the hypothalamic level. Aim 2: Determine the role of hypothalamic Sirt1 in the regulation of the Prohormone Convertases 1 and 2. To this purpose we will test the following hypotheses: 1. Sirt1 regulates PC1 and PC2 in N43 hypothalamic cells 2. Sirt1 regulates the PC's in POMC and AgRP neurons in the arcuate nucleus. 3. The regulation of PC2 causes a decrease in 1-MSH levels and aggravates the DIO condition. Aim 3: Determine the role of hypothalamic Sirt1 in the diet-induced obesity (DIO) condition. To this purpose we will investigate the following hypotheses: 1. Food intake of DIO rats is sensitive to inhibition of hypothalamic Sirt1. 2. Exposure to High Fat Diet (HFD) alters hypothalamic Sirt1 expression, signaling, and Sirt1 co- substrate/activator NAD+ levels. 3. The inhibitory effect of Sirt1 on mTOR signaling in the DIO condition is one of the causes of obesity. PUBLIC HEALTH RELEVANCE: According to the World Health Organization, obesity in developed countries has reached epidemic proportions. There are globally more than 1 billion adults overweight, with around 300 million of them clinically obese. As a consequence, the study of obesity has become a priority in medical research. Still, the search for effective anti-obesity drugs has been unsuccessful. Initially, the discovery of the hormone leptin raised a lot of expectations, given its capacity to decrease appetite and body weight of obese leptin deficient mice. However, it was soon established that most obese humans and rodents have high levels of plasma leptin, which fail to reduce appetite and body weight. Many aspects of this leptin-resistant state are still unknown. A better understanding of leptin molecular mechanisms affecting neural circuits is essential to develop new strategies for the treatment of obesity. Very recently, the discovery of nutrient sensors took a big stage in the obesity research. Aside from mTOR (mammalian target of rapamycin) and AMPK (AMP activated kinase), known to be important energy/nutrient sensors, the enzyme Sirt1, known to be involved in many biological processes including cellular differentiation, apoptosis, metabolism, and aging, now has another potential role as energy sensor. Therefore, this proposal provides a novel view assigned to Sirt1 as a cellular energy sensor regulating energy balance at the hypothalamic level.

描述(申请人提供)：肥胖及其相关的医疗并发症，包括II型糖尿病、心血管疾病、血脂异常和癌症，在美国每年造成30多万人死亡。肥胖症治疗策略往往不能带来足够的持续体重减轻，而且美国和许多其他国家的肥胖症患病率和严重程度正在逐渐增加。最近的调查将大约三分之一的美国人归类为肥胖。肥胖状况的复杂性是环境和易感遗传因素相互作用的结果。对肥胖发病机制和能量代谢调节的分子机制有更深入的了解，对于开发有效的治疗方法是至关重要的。能量平衡是由感知并对身体营养状态做出反应的组织和器官维持的。在中枢层面，下丘脑是解释肥胖或营养相关输入的神经系统的主要组成部分；它提供荷尔蒙和行为反应，最终目的是调节能量摄入和消耗。在分子水平上，被称为营养或能量传感器的酶模拟了参与能量平衡的组织的作用。两个关键的能量/营养感应器，mTOR(哺乳动物雷帕霉素的靶标)和AMPK(AMP激活的激酶)-除了在周围组织中广泛的代谢作用-参与控制下丘脑的食物摄入量。Sirt1酶是一种进化保守的依赖NAD+的脱乙酰酶，参与细胞分化、细胞凋亡、新陈代谢和衰老等多种生物学过程。由于对NAD+的依赖，Sirt1还可以作为营养/氧化还原传感器发挥作用。因此，我们假设Sirt1可能通过影响下丘脑水平的mTOR或AMPK通路，在能量平衡控制中发挥作用。我们的初步结果表明，药物抑制下丘脑Sirt1或siRNA介导的下丘脑弓状核(ARC)Sirt1基因的下调减少了摄食量和体重增加。因此，本研究为Sirt1作为细胞能量感受器在下丘脑水平调节能量平衡提供了一个新的视角。SIRT1在下丘脑水平上将营养的可获得性与能量平衡联系起来，这一效应至少部分依赖于禁食诱导和Sirt1介导的FoxO1去乙酰化和mTOR信号的调节。基于这些发现，我们将：目标1：确定下丘脑Sirt1信号调节能量平衡的作用靶点和机制。为此，我们将确定：1.SIRT1是否通过FoxO1以营养依赖的方式调节厌食性POMC以及厌氧性刺激性相关肽(AgRP)和神经肽Y(NPY)。2.SIRT1以营养敏感的方式去乙酰化和抑制STAT3。3.SIRT1在下丘脑水平抑制mTOR信号转导。目的：确定下丘脑Sirt1在调节前激素转换酶1和2中的作用。为此，我们将检验以下假设：1.SIRT1调节下丘脑N43细胞中的PC1和PC2。2.SIRT1调节POMC中的PC和弓状核中的AgRP神经元。3.PC2的调节导致1-MSH水平下降，加重DIO病情。目的3：探讨下丘脑Sirt1在饮食诱导肥胖(DIO)中的作用。为此，我们将研究以下假设：1.DIO大鼠的进食对下丘脑Sirt1的抑制很敏感。2.高脂饮食(HFD)可改变下丘脑Sirt1的表达、信号和Sirt1共底物/激活物NAD+水平。3.在DIO状态下，Sirt1对mTOR信号的抑制作用是肥胖的原因之一。 与公共健康相关：根据世界卫生组织的数据，发达国家的肥胖症已经达到了流行的程度。全球有超过10亿成年人超重，其中约3亿人患有临床肥胖症。因此，肥胖的研究已经成为医学研究的优先事项。尽管如此，寻找有效的减肥药物仍未成功。最初，瘦素激素的发现提高了很多人的期望，因为它能够降低肥胖瘦素缺乏小鼠的食欲和体重。然而，人们很快就证实，大多数肥胖的人类和啮齿动物的血浆瘦素水平都很高，这无法减少食欲和体重。这种瘦素抵抗状态的许多方面仍然未知。更好地了解瘦素影响神经回路的分子机制对于开发治疗肥胖症的新策略至关重要。最近，营养传感器的发现在肥胖研究中占据了很大的地位。除了mTOR(雷帕霉素的哺乳动物靶标)和AMPK(AMP激活的激酶)，Sirt1酶是已知的重要的能量/营养感受器，它参与了许多生物过程，包括细胞分化、细胞凋亡、代谢和衰老，现在又有另一个潜在的能量感应器作用。因此，本研究为Sirt1作为细胞能量感受器在下丘脑水平调节能量平衡提供了一个新的视角。