Sim1 Function in Feeding Regulation

描述(申请人提供)：肥胖是一个主要的公共卫生问题。SIM1是已知的六个人类基因之一，当突变时会导致严重肥胖。SIM1编码一个基本的螺旋-环-螺旋-PAS(bHLH-PAS)转录因子，对包括室旁核(PVN)在内的下丘脑某些区域的发育程序是必不可少的。SIM1也在发育后的下丘脑室旁核中表达，它可能在生理上调节食物的摄入量。在SIM1(杂合子)基因敲除小鼠中，SIM1的剂量减少了一半(单倍体不足)，比对照组吃了更多的食物，出现肥胖，呈线性增长，当受到高热量、高脂肪饮食的挑战时，他们的食物摄入量没有显示出正常的减少。所有这些异常也可以在突变干扰下丘脑信号的小鼠身上看到，这些突变通过黑素皮质素4受体(MC4R)在PVN内或投射到PVN的神经元中大量表达。MC4R突变是导致人类严重早发性肥胖的最常见的遗传原因。SIM1小鼠对黑素皮质素激动剂的反应表现出PVN神经元的激活缺陷。关于Sim1单倍体不足如何导致Mc4r信号缺陷以及这些变化如何与相关的吞噬过度和肥胖相关的关键问题仍未得到解答。Sim1单倍体不足的代谢效应是下丘脑发育异常的结果，还是次要于转录因子尚未确定的发育后作用？哪些下丘脑室旁核神经元负责Sim1小鼠的吞噬功能？如果Sim1对进食行为的影响是由于它在成年人身上的作用，那么由Sim1转录调控的基因就成为治疗干预的潜在靶点，以减少过度吞噬和饮食诱导的肥胖。这项建议的目的是解决Sim1小鼠过度肥胖和Mc4r信号受损的机制。第一个目标将确定Sim1小鼠的PVN神经元是否具有正常的细胞数量、后脑投射和Mc4r表达。第二个目的是直接测试Sim1是否在发育后期导致高血压性肥胖。最终目的是测试Sim1是否通过作用于表达催产素、TRH或CRH的PVN神经元的特定亚群来调节摄食行为。这些目标的完成将有助于将SIM1作为单基因肥胖基因的发现转化为预防和治疗常见肥胖症及其相关发病率的改进。与公共卫生相关：肥胖是一项重大的公共卫生挑战，其后遗症包括糖尿病和心血管疾病。更好地理解能量平衡的分子生理学对于开发有效的肥胖症治疗方法至关重要。这项拟议的项目将描绘大脑中调节食物摄入量的分子机制。

DESCRIPTION (provided by applicant): Obesity is a major public health issue. SIM1 is one of six known human genes that when mutated cause severe obesity. SIM1 encodes a basic helix-loop-helix-PAS (bHLH-PAS) transcription factor essential for the developmental program of certain regions of the hypothalamus, including the paraventricular nucleus (PVN). SIM1 is also expressed post-developmentally in the PVN, where it may act physiologically to regulate food intake. Sim1 (heterozygous) knockout mice, in which the dosage of Sim1 is reduced by half (haploinsufficiency), eat more food than controls, develop obesity, show increased linear growth, and do not show a normal reduction in the mass of food they consume when challenged with a calorically dense, high fat diet. All of these abnormalities are also seen in mice with mutations that interfere with hypothalamic signaling via the melanocortin 4 receptor (MC4R), which is abundantly expressed in neurons within or projecting to the PVN. MC4R mutations are the most common genetic cause of severe, early onset human obesity. Sim1 mice show defective activation of PVN neurons in response to a melanocortin agonist. Key questions remain unanswered regarding how Sim1 haploinsufficiency results in defective Mc4r signaling and how these changes relate to the associated hyperphagia and obesity. Are the metabolic effects of Sim1 haploinsufficiency a consequence of aberrant hypothalamic development, or are they secondary to yet-to-be-characterized post-developmental actions of the transcription factor? Which PVN neurons are responsible for the hyperphagia of Sim1 mice? If the effects of Sim1 on feeding behavior are due to its actions in adults, genes that are transcriptionally regulated by Sim1 become potential targets for therapeutic interventions to reduce hyperphagia and diet-induced obesity. The aims of this proposal address the mechanism of hyperphagic obesity and impaired Mc4r signaling in Sim1 mice. The first aim will determine whether PVN neurons in Sim1 mice have normal cell numbers, hindbrain projections, and Mc4r expression. The second aim tests directly whether Sim1 acts post-developmentally to cause hyperphagic obesity. The final aim tests whether Sim1 regulates feeding behavior by acting in specific subsets of PVN neurons expressing oxytocin, Trh, or Crh. Completion of these aims will facilitate translating the discovery of SIM1 as a monogenic obesity gene into improvements in prevention and treatment of common obesity and its associated morbidity. PUBLIC HEALTH RELEVANCE: Obesity, sequelae of which include diabetes mellitus and cardiovascular disease, is a major public health challenge. A better understanding of the molecular physiology of energy balance is critical to the development of effective therapeutics for obesity. The proposed project will delineate molecular mechanisms within the brain that regulate food intake.