Sim1 Function in Feeding Regulation

Sim1 饲喂调节功能

• 批准号: 8249887
• 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/8249887
• 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）：肥胖是一个重大的公共卫生问题。 SIM1 是已知的六种人类基因之一，突变后会导致严重肥胖。 SIM1 编码一种基本的螺旋-环-螺旋-PAS (bHLH-PAS) 转录因子，对于下丘脑某些区域（包括室旁核 (PVN)）的发育程序至关重要。 SIM1 也在发育后的 PVN 中表达，它可能在生理上发挥作用来调节食物摄入。 Sim1（杂合）敲除小鼠，其中 Sim1 的剂量减少一半（单倍剂量不足），比对照组吃更多的食物，出现肥胖，表现出线性生长增加，并且在以下情况下它们消耗的食物质量没有表现出正常的减少：面临热量密集、高脂肪饮食的挑战。所有这些异常现象也出现在携带突变的小鼠中，这些突变通过黑皮质素 4 受体 (MC4R) 干扰下丘脑信号传导，该受体在 PVN 内或投射到 PVN 的神经元中大量表达。 MC4R 突变是严重、早发性人类肥胖的最常见遗传原因。 Sim1 小鼠在黑皮质素激动剂的作用下表现出 PVN 神经元激活缺陷。关于 Sim1 单倍体不足如何导致 Mc4r 信号传导缺陷以及这些变化如何与相关的食欲亢进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，还是继发于转录因子尚未表征的发育后作用？哪些 PVN 神经元与 Sim1 小鼠的食欲亢进有关？如果 Sim1 对进食行为的影响是由于其在成人中的作用，那么受 Sim1 转录调控的基因将成为减少食欲过盛和饮食引起的肥胖的治疗干预的潜在目标。该提案的目的是解决 Sim1 小鼠贪食性肥胖和 Mc4r 信号传导受损的机制。第一个目标是确定 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。第二个目标直接测试 Sim1 是否在发育后发挥作用，导致食欲过盛肥胖。最终目标测试 Sim1 是否通过作用于表达催产素、Trh 或 Crh 的 PVN 神经元的特定子集来调节进食行为。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普通肥胖及其相关发病率的预防和治疗的改进。公共卫生相关性：肥胖及其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。更好地了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。拟议的项目将描述大脑内调节食物摄入的分子机制。