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

描述（由申请人提供）：该项目基于最近获得的数据，证明FosB和其他FosB拮抗剂以及中枢神经系统中AP1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。我们已经部分探索过表达FosB的小鼠的骨骼和脂肪表型之间的联系（Kveiborg et al., 2004; Sabatakos et al., 2000）。然而，我们最近的两项研究，一项是上个月发表的（Rowe et al., 2009），另一项是准备提交的（见附录ASBMR摘要，2009），已经产生了一些非常令人兴奋的新数据，我们认为这些数据值得进一步调查，并可能导致高度创新的发现，不仅在骨质疏松症，而且在肥胖和糖尿病方面具有重要意义。简而言之，第一项研究表明，具有高骨量的ENO2-(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。这与降低胰岛素水平、增加胰岛素敏感性和改善葡萄糖耐量有关。由于将（FosB）靶向脂肪细胞未能模仿这种表型，我们随后转向了能量的中枢调节。在第二项研究中，在ENO2启动子控制下，下丘脑腹侧靶向表达FosB或构建AP1拮抗剂（Dominant Negative JunD）再现了过表达FosB的小鼠的整个表型，导致能量消耗增加，身体活动减少，脂肪量减少，骨形成和骨量显著增加。因此，本应用的具体目的是确定受下丘脑FosB（或工程化DNJunD）表达影响的神经元回路。FosB是AP1转录因子家族的拮抗剂，可通过增加能量消耗和随后减少脂肪量来强烈诱导骨形成。因此，在本应用中提出的实验可能导致鉴定调节骨形成的新途径和药物发现的新靶点，可能为骨质疏松症的合成代谢治疗干预提供新方法，但也可能为肥胖和糖尿病的病理生理学提供一些启示。

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.