pRb Function in Mediobasal Hypothalamus in Diet Induced Obesity

饮食引起的肥胖中下丘脑内侧基底区的 pRb 功能

• 批准号: 9977171
• 负责人: STREAMSON C CHUA
• 金额: $ 56.95万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-10 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9977171
• 关键词: Apoptosis; Applications Grants; Blood - brain barrier anatomy; Blood Circulation; Body Weight; Brain; CDK4 gene; Cell Cycle; Cell Nucleus; Cell Proliferation; Cells; Cyclin D1; Cyclin-Dependent Kinase Inhibitor 2A; Diet; Disease; Epidemic; Equilibrium; Etiology; Exposure to; Fatty acid glycerol esters; Functional disorder; Gene Expression; Genes; Health; High Fat Diet; Homeostasis; Hypothalamic structure; Impairment; Injections; Knowledge; LEPR gene; Leptin; Mitotic; Modeling; Modernization; Molecular; Mus; Mutation; Natural regeneration; Neurons; Obesity; POMC gene; Pharmacology; Phenotype; Phosphorylation; Play; Reducing diet; Reproducibility of Results; Research; Retinoblastoma Protein; Role; Structure of nucleus infundibularis hypothalami; Testing; Tumor Suppression; Tumor Suppressor Proteins; Wild Type Mouse; cancer therapy; energy balance; feeding; functional disability; improved; leptin receptor; malignant breast neoplasm; median eminence; neurogenesis; obesity treatment; preservation; receptor; trend; tumorigenesis

Abstract Obesity is a present and increasing worldwide health threat. The vast majority of obese people contain higher levels of leptin in the circulation, which can be modeled in wild type mice on high fat diet (HFD) to promote diet induced obesity (DIO). Positive energy imbalance in the presence of higher leptin levels indicates reductions in leptin action, which likely contribute to DIO. In this application, we propose to gain better understanding of leptin action reduction in DIO. Major leptin target neurons that regulate energy balance are localized in mediobasal hypothalamus (MBH), which is exposed to the circulation due to the incomplete blood-brain barrier at the Median Eminence. Byproducts in circulation following HFD could therefore impair MBH neuron homeostasis, which we define as a healthy balance of post-mitotic quiescence, proliferation, survival, neurogenesis, and differentiation. The tumor suppressor pRb is a central regulator of cellular homeostasis, we propose to apply the knowledge of pRb function in tumor suppression to study homeostasis of MBH neurons in DIO. We obtained evidence that HFD induces pRb phosphorylation and inactivation in MBH neurons. We then tested the effects of expressing an un-phosphorylable pRb (pRbΔP) in MBH to preserve pRb function in DIO, and found significantly reduced DIO. In this MPI RO1 application, we propose to (1) determine the mechanisms of pRbΔP function in MBH to inhibit DIO, (2) determine the anti-DIO effects of pRbΔP when expressed in POMC neurons, (3) identify non-POMC neurons in MBH that contribute to inhibition of DIO when pRbΔP is expressed in MBH and determine the underlying mechanisms, and (4) determine the translational potential of our finding that expressing pRbΔP in MBH can inhibit DIO.

摘要 肥胖症是一个目前和日益严重的全球性健康威胁。绝大多数肥胖者体内含有较高的 循环中的瘦素水平，其可以在高脂肪饮食（HFD）的野生型小鼠中建模以促进饮食 肥胖症（DIO）。在较高瘦素水平存在下的正能量失衡表明减少 瘦素作用，这可能有助于DIO。在本申请中，我们建议更好地理解 DIO中瘦素作用降低。调节能量平衡的主要瘦素靶神经元位于 下丘脑内侧基底部（MBH），由于血脑屏障不完整而暴露于循环 在中央隆起。因此，HFD后循环中的副产物可损害MBH神经元 稳态，我们将其定义为有丝分裂后静止、增殖、存活的健康平衡， 神经发生和分化。肿瘤抑制基因pRb是细胞内环境稳定的中心调节因子， 建议将pRb在肿瘤抑制中的功能的知识应用于研究MBH神经元的稳态， DIO。我们获得的证据表明，HFD诱导MBH神经元pRb磷酸化和失活。然后我们 测试了在MBH中表达不可磷酸化的pRb（pRbΔP）以在DIO中保留pRb功能的作用， 并发现DIO显著降低。在这个MPI RO 1应用程序中，我们建议（1）确定 pRbΔP在MBH中抑制DIO的作用机制，（2）确定pRbΔP在以下情况下的抗DIO作用： 在POMC神经元中表达，（3）鉴定MBH中有助于抑制DIO的非POMC神经元， pRbΔP在MBH中表达，并决定其潜在机制;（4）决定MBH的翻译 我们发现在MBH中表达pRbΔP可以抑制DIO。