Role of Sim1 in Hyperphagic Obesity

Sim1 在暴食性肥胖中的作用

• 批准号: 7146465
• 负责人: BASSIL M KUBLAOUI
• 金额: $ 12.26万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7146465
• 关键词: behavioral /social science research tag; behavioral genetics; bioenergetics; brain mapping; cell line; gene expression profiling; genetic mapping; genetic regulation; genetically modified animals; immunocytochemistry; in situ hybridization; laboratory mouse; melanocyte stimulating hormone; microarray technology; nutrient intake activity; nutrition related tag; obesity; overeating; small interfering RNA

DESCRIPTION (provided by applicant): Broadly this project's goals are to better understand the neuroendocrine regulation of energy balance. Obesity in the U.S. is an epidemic with 65% of adults and 25% of children being overweight or obese. This project began with the identification of a novel form of monogenic obesity in a child with a balanced translocation disrupting a gene called SIM1. The Sim1 heterozygous knock out mouse is also hyperphagic, and obese. SIM1 is expressed in the hypothalamus, mostly in the paraventricular nucleus. We aim to define the molecular function of SIM1 in feeding regulation as it relates to known hypothalamic pathways. Sim1 heterozygous mice have the phenotypic constellation suggested to be a hallmark of defective melanocortin signaling, namely hyperphagia, obesity, increased length, and a sensitivity to high fat. This constellation is not only found in melanocortin-4 receptor-/- (mc4r-/-) mice and Agouti Yellow mice (Ay) but also in mice deficient in bdnf (brain derived neurotrophic factor) and its receptor. We showed that unlike mc4r-/- mice, Sim1 heterozygotes have a normal energy expenditure. They are resistant to the anorectic effect of MTII, a potent Mc4r agonist, but not its effect of energy expenditure. They fail to activate PVN neurons in response to MTII, suggesting a divergence between feeding and energy expenditure, with Mc4r neurons in the PVN regulating feeding and Mc4r neurons elsewhere in the CNS regulating energy expenditure. We will use Sim1 GFP mice to examine colocalization of Sim1, MTII induced c-fos, and oxytocin. We will use various molecules to attempt to rescue the Sim1 obesity phenotype. We will attempt to identify gene targets of SIM1 after knocking down SIM1 expression in a hypothalamic cell line and performing a gene array. The anticipated outcome of these experiments will place Sim1 in known molecular and physiologic pathways that regulate food intake. These results could lead to new targets for pharmacologic agents to prevent or treat obesity and its sequelae such as type 2 diabetes mellitus and coronary artery disease, major public health threats in the United States and other developed nations. The relevance of this project to public health is that it studies obesity, a major public health concern. We are trying understand how the brain regulates our eating behavior. We study a gene that was found to cause morbid obesity in a girl. We are using a mouse model of this gene to understand how it causes obesity.

描述（由申请人提供）： 总体而言，该项目的目标是更好地了解能量平衡的神经内分泌调节。肥胖在美国是一种流行病，65% 的成年人和 25% 的儿童超重或肥胖。该项目首先在一名儿童中鉴定出一种新型单基因肥胖症，该儿童的平衡易位破坏了 SIM1 基因。 Sim1 杂合基因敲除小鼠也贪食且肥胖。 SIM1在下丘脑表达，主要在室旁核表达。我们的目标是定义 SIM1 在摄食调节中的分子功能，因为它与已知的下丘脑通路相关。 Sim1 杂合小鼠的表型星座被认为是黑皮质素信号传导缺陷的标志，即食欲过盛、肥胖、体长增加和对高脂肪敏感。这种现象不仅存在于黑皮质素 4 受体-/- (mc4r-/-) 小鼠和刺鼠黄小鼠 (Ay) 中，而且还存在于 bdnf（脑源性神经营养因子）及其受体缺陷的小鼠中。我们发现，与 mc4r-/- 小鼠不同，Sim1 杂合子具有正常的能量消耗。它们对 MTII（一种有效的 Mc4r 激动剂）的厌食作用有抵抗力，但对能量消耗的影响没有抵抗力。它们无法响应 MTII 激活 PVN 神经元，这表明进食和能量消耗之间存在差异，PVN 中的 Mc4r 神经元调节进食，而 CNS 中其他地方的 Mc4r 神经元调节能量消耗。我们将使用 Sim1 GFP 小鼠来检查 Sim1、MTII 诱导的 c-fos 和催产素的共定位。我们将使用各种分子来尝试拯救 Sim1 肥胖表型。在敲除下丘脑细胞系中的 SIM1 表达并进行基因阵列后，我们将尝试识别 SIM1 的基因靶点。这些实验的预期结果将把 Sim1 置于调节食物摄入的已知分子和生理途径中。这些结果可能会为预防或治疗肥胖及其后遗症（例如 2 型糖尿病和冠状动脉疾病）的药物制定新的目标，这些后遗症是美国和其他发达国家的主要公共卫生威胁。该项目与公共卫生的相关性在于它研究肥胖这一主要的公共卫生问题。我们正在尝试了解大脑如何调节我们的饮食行为。我们研究了一种导致女孩病态肥胖的基因。我们正在使用该基因的小鼠模型来了解它如何导致肥胖。