Sim1 Function in Feeding Regulation

Sim1 饲喂调节功能

• 批准号: 7655806
• 负责人: Andrew R. Zinn
• 金额: $ 37.68万
• 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/7655806
• 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; Helix-Turn-Helix Motifs; Homeostasis; Human; Hyperphagia; Hypothalamic structure; In Situ Hybridization; Knockout Mice; Label; Lasers; Measures; Melanocortin 4 Receptor; Melanocortin 4 receptor mutation; 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; public health relevance; 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。 SIM1是六个已知的人类基因之一，当突变引起严重的肥胖症时。 SIM1编码对下丘脑某些区域的发展程序至关重要的基本螺旋 - 环 - 螺旋 - 螺旋 - 螺旋 - 螺旋 - 螺旋 - 螺旋 - 螺旋（BHLH-PAS）的转录因子，包括旁脑核（PVN）。 SIM1在PVN中也在后发达，在该PVN中可以在生理上起作用以调节食物摄入量。 SIM1（杂合）基因敲除小鼠，其中SIM1的剂量减少了一半（单倍次弥补），多吃食物，而不是对照，肥胖，表现出增加的线性生长，并且没有表现出正常的质量减少食物的正常减少，当他们在热量浓密，高脂肪饮食时挑战时消耗的食物消耗。在小鼠中也可以看到所有这些异常，这些突变通过黑素皮质素4受体（MC4R）干扰下丘脑信号传导，该突变在内部神经元中大量表达或投射到PVN中。 MC4R突变是严重，早期发作的最常见遗传原因。 SIM1小鼠响应黑色素皮质激动剂而显示出PVN神经元的有缺陷激活。关于SIM1单倍不足如何导致有缺陷的MC4R信号以及这些变化与相关的超晶状体和肥胖的关系，关键问题仍未得到答案。 SIM1单倍不足的代谢作用是下丘脑发育异常的结果，还是继发于转录因子的尚未表征的后发育后作用？哪些PVN神经元负责SIM1小鼠的倍率？如果SIM1对喂养行为的影响是由于其在成年人中的作用引起的，则在转录下受SIM1调节的基因成为降低肥大和饮食诱发的肥胖症的治疗干预措施的潜在靶标。该提案的目的涉及SIM1小鼠中肥大肥胖的机理和MC4R信号受损。第一个目的将确定SIM1小鼠中的PVN神经元是否具有正常的细胞数，后脑投影和MC4R表达。第二个目标直接测试SIM1是否在发达后起作用以引起倍感肥胖。最终目标测试SIM1是否通过在表达催产素，TRH或CRH的PVN神经元的特定子集中作用来调节进食行为。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共同肥胖及其相关的发病率的改善。公共卫生相关性：肥胖症，后遗症包括糖尿病和心血管疾病，是一个主要的公共卫生挑战。更好地了解能量平衡的分子生理学对于开发有效的肥胖治疗剂至关重要。拟议的项目将描述调节食物摄入量的大脑中的分子机制。