pRb Function in Mediobasal Hypothalamus in Diet Induced Obesity

摘要 肥胖是当今世界范围内一个日益严重的健康威胁。绝大多数肥胖者体内的 循环中瘦素水平，这可以在高脂饮食(HFD)促进饮食的野生型小鼠中建立模型 诱导性肥胖(DIO)。瘦素水平较高时，正能量失衡表明瘦素水平降低 瘦素的作用，这可能是DIO的原因。在本应用程序中，我们建议更好地了解 瘦素在DIO中的作用减少。瘦素调节能量平衡的主要靶神经元定位于 内侧基底下丘脑(MBH)，由于血脑屏障不完整而暴露在循环中 在中位数Eminence。因此，HFD后循环中的副产物可能会损害MBH神经元 动态平衡，我们将其定义为有丝分裂后的静止、增殖、存活、 神经发生和分化。肿瘤抑制因子pRb是细胞内稳态的中心调节因子，我们 建议应用pRb在肿瘤抑制中的作用研究MBH神经元的动态平衡。 我的天。我们获得了HFD诱导MBH神经元PRB磷酸化和失活的证据。然后我们 检测了在MBH中表达非磷酸化pRb(pRbΔP)对保存pRb功能的效果， 发现DIO显著降低。在此MPI RO1应用程序中，我们建议(1)确定 MBH中pRb-Δ-P抑制脱氧核糖核酸的作用机制：(2)决定pRb-Δ-P抗脱氧核糖核酸的作用 在POMC神经元中表达，(3)识别MBH中与DIO抑制有关的非POMC神经元 PRbΔP是以mbh表达的，决定了潜在的机制，以及(4)决定了翻译 我们发现在MBH中表达pRbΔP可以抑制DIO。

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.