Novel Anti-Diabetic Actions of Hypothalamic FGF19-FGFR1 Signaling

描述（由申请方提供）：葡萄糖激发后，胰岛素依赖性和非胰岛素依赖性机制均有助于血糖浓度恢复至基线水平。被称为葡萄糖有效性（GE）的胰岛素非依赖性组分与胰岛素一样有助于总体葡萄糖稳态，但它被视为固定的且在很大程度上不受调节的过程，因此不是研究者的研究焦点。然而，最近的一些观察结果提供了大脑通过胰岛素非依赖性机制有效诱导葡萄糖降低的能力的证据。我们的初步数据显示，在瘦素缺乏的ob/ob小鼠中，侧脑室（icv）注射抗糖尿病激素成纤维细胞生长因子19（FGF 19）可迅速使葡萄糖耐量正常化，尽管对胰岛素分泌或胰岛素敏感性没有影响。相反，这种效应完全由GE的选择性3倍增加介导。尽管这种效应背后的外周机制尚不清楚，但我们的数据强烈暗示了葡萄糖通过胰岛素非依赖性机制被外周组织吸收，随后代谢为乳酸，随后释放回循环的过程。在此背景下，我们提出了具体目标1：确定FGF 19如何增加胰岛素非依赖性葡萄糖处置。该目的的研究将1）量化这种脑介导的葡萄糖摄取增加和响应于FGF 19代谢为乳酸盐，2）确定其解释相关GE增加的程度，和3）鉴定其发生的组织。这些目标将在小鼠中使用从高血糖钳夹到代谢组学和生化分析的方法的组合来实现。 减肥手术的抗糖尿病效果是否也与此类似？啮齿类动物的数据表明大脑参与了减肥手术的降糖作用，在某些情况下，降糖涉及胰岛素非依赖性机制和胰岛素依赖性机制。此外，减肥手术增加了FGF 19从胃肠道的分泌。基于这些考虑，我们提出了具体目标2：确定GE增加是否有助于减肥手术的抗糖尿病作用。这方面的研究将 确定减肥手术是否激活类似于FGF 19参与的CNS机制，包括刺激胰岛素非依赖性葡萄糖摄取，然后转化为乳酸，然后释放到循环中。 我们发现，FGF 19在大脑中的作用迅速、有效且选择性地增加非胰岛素依赖性葡萄糖处置，这确定了一种新型的、CNS驱动的机制，对人类糖尿病的发病机制和治疗具有翻译意义。本提案中的研究旨在阐明这是如何发生的，以及它在多大程度上解释了减肥手术的抗糖尿病作用。

DESCRIPTION (provided by applicant): Following a glucose challenge, both insulin-dependent and -independent mechanisms contribute to the return to baseline blood glucose concentrations. Referred to as glucose effectiveness (GE), the insulin- independent component contributes as much to overall glucose homeostasis as insulin, but it has been viewed as a fixed and largely unregulated process and hence has not been a research focus for investigators. Several recent observations, however, offer evidence of the brain's capacity to potently induce glucose lowering via insulin-independent mechanisms. Adding to this work is our preliminary data showing that in leptin-deficient ob/ob mice, intracerebroventricular (icv) injection of the ani-diabetic hormone fibroblast growth factor-19 (FGF19) rapidly normalizes glucose tolerance despite having no effect on either insulin secretion or insulin sensitivity. Instead, this effect i mediated entirely by a selective, 3-fold increase of GE. Although the peripheral mechanism underlying this effect is unknown, our data strongly implicate a process whereby glucose is taken up into peripheral tissues via an insulin-independent mechanism, followed by its metabolism to lactate that is subsequently released back into circulation. With this background, we propose Specific Aim 1: To determine how FGF19 increases insulin-independent glucose disposal. Studies in this aim will 1) quantify this brain- mediated increase of glucose uptake and metabolism to lactate in response to FGF19, 2) determine the extent to which it explains the associated increase of GE, and 3) identify the tissues in which it occurs. These goals will be accomplished in mice using a combination of methods ranging from hyperglycemic clamp to metabolomics and biochemical analyses. Could a similar process contribute to the anti-diabetic effects of bariatric surgery? Rodent data implicate the brain in the glucose-lowering effects of bariatric procedures, and in some cases, glucose lowering involves insulin-independent as well as insulin-dependent mechanisms. Moreover, bariatric procedures increase FGF19 secretion from the GI tract. Based on these considerations, we propose Specific Aim 2: To determine if increased GE contributes to the anti-diabetic effect of bariatric surgery. Studies in this aim will determine if bariatric surgery activates CNS mechanisms analogous to those engaged by FGF19, including stimulation of insulin-independent glucose uptake, followed by conversion to lactate, which is then released into circulation. Our finding that FGF19 action in the brain rapidly, potently and selectively increases insulin-independent glucose disposal identifies a novel, CNS-driven mechanism with translational implications for both the pathogenesis and treatment of human diabetes. Studies in this proposal seek to clarify how this occurs and the extent to which it explains the anti-diabetic effect of bariatric surgical procedures.