Brain VDR Regulate Glucose Balance

我们对维生素D如何调节血糖缺乏了解，阻碍了它作为一种有效的糖尿病的使用 心理治疗。我们已经证明，维生素D可以在大脑中起作用，降低血糖水平，并减少维生素D的损失 大脑下丘脑室旁核(PVH)内的受体(VDR)对正常血糖至关重要 肥胖，但不是瘦的动物体内的水平。然而，VDRPVH神经元的神经回路/功能， PVH VDR对膳食维生素D的反应，以及在肥胖但不瘦状态下潜在影响的机制是 未知。这就提出了有关维生素D受体如何调节葡萄糖平衡的基本问题。我们有 建立了VDR阳性细胞表达Cre重组酶的遗传性小鼠模型(VDRCre)。这 为确定VDRPVH的功能、必要性和下游神经元靶点提供了一个极好的模型 神经元。此外，利用其他遗传工具，我们可以确定PVH内的VDR是否对 饮食中维生素D引起的血糖变化。最后，我们可以利用这些工具来确定其机制 大脑中维生素D对葡萄糖调节的潜在体重特异性影响。这笔赠款的目的是 目的：探讨维生素D对脑内葡萄糖平衡的影响机制。我们假设VDR调节 血糖水平通过不同的神经元回路和PVH神经元的基因组效应来实现。中环 假设将通过三个特定的目的来检验：1)确定PVH VDR阳性的神经元机制 神经元；2)确定PVH VDR对于饮食中维生素D在葡萄糖中的变化是必需的还是足够的 动态平衡；以及3)在肥胖模型中建立维生素D的血糖保护作用的机制。 在目标1中，我们将使用化学遗传学、单细胞基因组学和免疫组织化学来确定 VDRPVH神经元的功能、识别和回路。在目标2中，我们将使用不同的饮食手法 维生素D测试PVH VDR是否是高维生素D诱导的血糖改善所必需的。另外， 我们将确定中央服用活性维生素D是否可以克服低饮食的有害影响 维生素D对葡萄糖平衡的影响。在目标3中，我们将确定肥胖如何改变转录和神经元 对活性维生素D(1，25D3)的激活反应。此外，我们将确定VDR是否存在差异 肥胖与瘦状态下VDR+神经元数量的比较。提出的研究是创新的，因为 它利用一只新的小鼠，研究了一种新的神经元群体(VDRPVH)在糖耐量中的作用 模特。拟议的研究具有重要意义，因为它有望确定需要理解的新范式 维生素D的作用，以及可能识别PVH中关键的葡萄糖调节的新回路 属性。这项研究的结果可能最终解释临床试验中使用的一些差异 维生素D作为一种治疗方法，并提供关键信息，以促进维生素D作为治疗剂的使用。 总之，我设想，这项提议的完成将推动这项研究朝着以下长期目标迈进 了解如何利用维生素D作为2型糖尿病的有效治疗方法。

Our lack of understanding regarding how vitamin D regulates glucose prevents its use as an effective diabetes therapy. We have shown that vitamin D can act in the brain to lower glucose levels and that loss of vitamin D receptors (VDR) within the paraventricular hypothalamus (PVH) of the brain are critical for normal glucose levels in obese, but not lean, animals. However, the neurocircuitry/function of VDRPVH neurons, the role of the PVH VDR responding to dietary vitamin D, and mechanisms underlying effects in obese but not lean states are unknown. This raises basic questions regarding how vitamin D receptors mediate glucose balance. We have generated a genetic mouse model with Cre recombinase expression in VDR positive cells (VDRCre). This provides an excellent model to determine the function, necessity, and downstream neuronal targets of VDRPVH neurons. Additionally, utilizing other genetic tools, we can determine if VDR within the PVH are necessary for changes in blood glucose by dietary vitamin D. Last, we can utilize these tools to determine the mechanisms underlying weight-specific effects of vitamin D in the brain on glucose regulation. The objective of this grant is to determine the mechanisms of vitamin D in the brain on glucose balance. We hypothesize that VDR regulate glucose levels through distinct neuronal circuits and through genomic effects in PVH neurons. The central hypothesis will be tested by three specific aims: 1) identifying neuronal mechanisms for PVH VDR positive neurons; 2) determining if PVH VDR are required or sufficient for dietary-vitamin D changes in glucose homeostasis; and 3) establishing mechanisms for the glucose-protective effect of vitamin D in an obese model. In Aim 1, we will use chemogenetics, single-cell genomics, and immunohistochemistry to determine the function, identity, and circuitry of VDRPVH neurons. In Aim 2, we will use different dietary manipulations of vitamin D to test if PVH VDR are necessary for high-vitamin D induced glucose improvements. Additionally, we will determine if central administration of active vitamin D can overcome deleterious effects of low dietary vitamin D on glucose balance. In Aim 3, we will determine how obesity alters the transcriptomic and neuronal activation response to active vitamin D (1,25D3). Additionally, we will determine if there are differences in VDR expression or VDR+ neuronal number in obese vs. lean states. The research proposed is innovative, because it investigates the function of a novel neuronal population (VDRPVH) on glucose tolerance, using a novel mouse model. The proposed research is significant because it is expected to identify new paradigms to understand vitamin D action, as well as possibly identifying a novel circuit in the PVH with critical glucose-regulating properties. Results from this research may ultimately explain some of the variance in clinical trials utilizing vitamin D as a therapy and provide critical information to advance the use of vitamin D as a therapeutic agent. Altogether, I envision that the completion of this proposal will move this research towards the long-term goal of understanding how to utilize vitamin D as an effective therapy for type 2 diabetes.