Sim1 Function in Feeding Regulation

Sim1 饲喂调节功能

• 批准号: 8055818
• 负责人: Andrew R. Zinn
• 金额: $ 33.47万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-20 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8055818
• 关键词: Address; Adult; Agonist; Alleles; Appetite Depressants; Biological Assay; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Cardiovascular Diseases; Cell Count; Defect; Development; Diabetes Mellitus; Diet; Eating; Energy Metabolism; Fatty acid glycerol esters; Feeding behaviors; Food; Genes; Genetic; Growth; Health; Helix-Turn-Helix Motifs; Homeostasis; Human; Hyperphagia; Hypothalamic structure; In Situ Hybridization; Knockout Mice; Label; Lasers; Measures; Melanocortin 4 Receptor; Melanocortin 4 receptor mutation; Messenger RNA; Metabolic; Molecular; Morbid Obesity; Morbidity - disease rate; Mus; Mutate; Mutation; Neuroanatomy; Neurons; Neuropeptides; Normal Cell; Nucleus solitarius; Obesity; Oxytocin; Pattern; Physiological; Physiology; Prevention; Public Health; Receptor Activation; Receptor Signaling; Regulation; Relative (related person); Reporter; Reverse Transcriptase Polymerase Chain Reaction; Role; Satiety Response; Secondary to; Signal Transduction; Staining method; Stains; Tamoxifen; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transgenes; Transgenic Organisms; Translating; common treatment; dosage; early onset; energy balance; feeding; hindbrain; paraventricular nucleus; postnatal; programs; promoter; receptor expression; recombinase; research study; response; selective expression; transcription factor

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.

描述（由申请人提供）：肥胖是一个主要的公共卫生问题。SIM 1是六种已知的人类基因之一，当突变时会导致严重的肥胖。SIM 1编码一种碱性螺旋-环-螺旋-PAS（bHLH-PAS）转录因子，对下丘脑某些区域（包括室旁核（PVN））的发育程序至关重要。SIM 1也在PVN中发育后表达，在PVN中它可以生理性地调节食物摄入。Sim 1（杂合）基因敲除小鼠，其中Sim 1的剂量减少一半（单倍不足），比对照组吃更多的食物，出现肥胖，显示出增加的线性生长，并且当用热量密集的高脂肪饮食进行攻击时，它们消耗的食物质量没有显示出正常的减少。所有这些异常也见于突变的小鼠，这些突变通过黑皮质素4受体（MC 4 R）干扰下丘脑信号传导，MC 4 R在PVN内或投射到PVN的神经元中大量表达。MC 4 R突变是严重的、早发性人类肥胖症的最常见遗传原因。Sim 1小鼠显示PVN神经元响应于黑皮质素激动剂的激活缺陷。关于Sim 1单倍不足如何导致Mc 4 r信号缺陷以及这些变化如何与相关的摄食过多和肥胖相关的关键问题仍未得到解答。Sim 1单倍不足的代谢效应是下丘脑发育异常的结果，还是转录因子发育后作用的结果？哪些PVN神经元负责Sim 1小鼠的摄食过度？如果Sim 1对进食行为的影响是由于其在成年人中的作用，那么由Sim 1转录调控的基因就成为治疗干预的潜在靶点，以减少摄食过多和饮食诱导的肥胖。该提案的目的是解决Sim 1小鼠中的贪食性肥胖和Mc 4 r信号转导受损的机制。第一个目标将确定Sim 1小鼠的PVN神经元是否具有正常的细胞数量、后脑投射和Mc 4 r表达。第二个目标是直接测试Sim 1是否在发育后引起了过度吞噬性肥胖。最终的目的是测试Sim 1是否通过作用于表达催产素、Trh或Crh的PVN神经元的特定子集来调节进食行为。这些目标的完成将有助于将SIM 1作为单基因肥胖基因的发现转化为预防和治疗常见肥胖及其相关发病率的改善。与公共卫生的关系：肥胖症的后遗症包括糖尿病和心血管疾病，是一项重大的公共卫生挑战。更好地理解能量平衡的分子生理学对于开发有效的肥胖疗法至关重要。该项目将描述大脑内调节食物摄入的分子机制。