AP1-dependent regulation of bone mass and energy expenditure in the hypothalamus

AP1 依赖性调节下丘脑骨量和能量消耗

• 批准号: 8173390
• 负责人: ROLAND E BARON
• 金额: $ 38.29万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-15 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173390
• 关键词: Adipocytes; Adult; Affect; Age; Aging; Applications Grants; Automobile Driving; Blood; Bone Density; Brain; Brain region; Cells; Data; Diabetes Mellitus; Dominant-Negative Mutation; Energy Metabolism; Engineering; Event; Exhibits; Family; Fatty acid glycerol esters; Figs - dietary; Functional disorder; Funding; Gene Targeting; Genetic; Genetic Transcription; Grant; Hypothalamic structure; Injection of therapeutic agent; Insulin; Investigation; Knock-out; Lead; Leptin; Light; Link; Measurable; Mediating; Mediator of activation protein; Mus; Neuraxis; Neurons; Obesity; Osteogenesis; Osteoporosis; Pathway interactions; Peripheral; Phenotype; Physical activity; Physiological; Protein Isoforms; Proteins; Publishing; RNA Splicing; Regulation; Role; Serotonin; Signal Transduction; Site; Skeleton; Testing; Therapeutic Agents; Therapeutic Intervention; Time; Transcription Factor AP-1; Work; abstracting; base; bone; bone mass; drug discovery; glucose tolerance; in vivo; innovation; insulin sensitivity; insulin signaling; mouse model; neuronal circuitry; novel; novel strategies; obesity treatment; osteoblast differentiation; overexpression; particle; programs; promoter; research study; response; transcription factor

DESCRIPTION (provided by applicant): This project is based on recently acquired data demonstrating a role for (FosB and other antagonists to FosB and the AP1 transcriptional machinery in the central nervous system to regulate on the one hand bone formation and on the other hand energy expenditure and fat. We had partially explored the link between the bone and fat phenotypes of mice overexpressing (FosB (Kveiborg et al., 2004; Sabatakos et al., 2000). However, two of our recent studies, one published last month (Rowe et al., 2009) and one being prepared for submission (see Appendix ASBMR Abstract, 2009), have generated some very exciting new data which in our view deserve further investigation and could lead to highly innovative findings with significant implications not only in osteoporosis but also in obesity and diabetes. Briefly, the first study demonstrated that ENO2-(FosB mice, which have high bone mass, exhibited an increase in energy expenditure leading to a decrease in adipocyte size and thereby fat mass. This was associated with decreased insulin levels, increased insulin sensitivity and better glucose tolerance. Since targeting (FosB to adipocytes failed to mimic the phenotype, we then turned to the central regulation of energy. In the second study, targeted expression of (FosB or a constructed AP1 antagonist (Dominant Negative JunD) in the ventral portion of the hypothalamus recapitulated the entire phenotype of mice overexpressing (FosB under the control of the ENO2 promoter, inducing an increase in energy expenditure, decreased physical activity, decreased fat mass and markedly increased bone formation and bone mass. The Specific Aim of this application are therefore to identify the neuronal circuit(s) affected by the hypothalamic expression of (FosB (or engineered DNJunD), antagonists of the AP1 family of transcription factors, which lead to strong induction of bone formation with an increase in energy expenditure and a subsequent reduction in fat mass. The experiments proposed in this application could therefore lead to the identification of novel pathways regulating bone formation and novel targets for drug discovery, potentially allowing new approaches for anabolic therapeutic intervention in osteoporosis, but could also shed some light on the pathophysiology of Obesity and Diabetes. PUBLIC HEALTH RELEVANCE: We have found that a protein, when expressed in a region of the brain called hypothalamus, decreases insulin in the blood, decreases fat in the body and increases the density of bones in the skeleton. We will identify how it works in the brain, potentially allowing new approaches for therapeutic intervention in osteoporosis, but this work could open new avenues for the treatment of obesity and diabetes.

描述（由申请人提供）：该项目基于最近获得的数据，这些数据证明了FosB和FosB的其他拮抗剂以及中枢神经系统中的AP 1转录机制一方面调节骨形成，另一方面调节能量消耗和脂肪。我们已经部分探索了过表达FosB的小鼠的骨和脂肪表型之间的联系（Kveiborg等人，2004; Sabatakos等人，2000年）。然而，我们最近的两项研究，一项是上个月发表的（Rowe等人，2009年）和一个正在准备提交（见附录ASBMR摘要，2009年），产生了一些非常令人兴奋的新数据，在我们看来，值得进一步研究，并可能导致高度创新的发现，不仅在骨质疏松症，而且在肥胖症和糖尿病的重大影响。简言之，第一项研究表明，具有高骨量的ENO 2-β FosB小鼠表现出能量消耗的增加，导致脂肪细胞大小减少，从而减少脂肪量。这与胰岛素水平下降、胰岛素敏感性增加和葡萄糖耐量改善有关。由于将FosB靶向脂肪细胞未能模拟表型，因此我们转向能量的中枢调节。在第二项研究中，在下丘脑腹侧部分靶向表达β FosB或构建的AP 1拮抗剂（显性阴性JunD）重现了在ENO 2启动子控制下过表达β FosB的小鼠的整个表型，诱导能量消耗增加，体力活动减少，脂肪量减少，骨形成和骨量显著增加。因此，本申请的具体目的是鉴定受转录因子的AP 1家族拮抗剂（FosB（或工程化DNJunD））的下丘脑表达影响的神经元回路，其导致骨形成的强烈诱导，伴随能量消耗的增加和随后的脂肪量的减少。因此，本申请中提出的实验可能导致确定调节骨形成的新途径和药物发现的新靶点，可能允许骨质疏松症合成代谢治疗干预的新方法，但也可能揭示肥胖和糖尿病的病理生理学。 公共卫生相关性：我们发现，当一种蛋白质在大脑中一个叫做下丘脑的区域表达时，它会减少血液中的胰岛素，减少体内的脂肪，增加骨骼中的骨密度。我们将确定它如何在大脑中工作，可能允许骨质疏松症治疗干预的新方法，但这项工作可能为治疗肥胖和糖尿病开辟新途径。