Novel Anti-Diabetic Actions of Hypothalamic FGF19-FGFR1 Signaling

描述(由申请人提供)：在血糖挑战之后，胰岛素依赖和非独立机制都有助于血糖浓度恢复到基线水平。被称为葡萄糖有效性(GE)的不依赖于胰岛素的成分对整体血糖稳态的贡献与胰岛素一样大，但它一直被视为一个固定的、基本上不受调控的过程，因此一直不是研究人员的研究重点。然而，最近的几项观察提供了证据，证明大脑有能力通过不依赖胰岛素的机制有效地诱导血糖下降。除了这项工作，我们的初步数据显示，在瘦素缺乏的ob/ob小鼠中，脑室(Icv)注射抗糖尿病激素成纤维细胞生长因子-19(FGF19)可迅速恢复正常的糖耐量，尽管对胰岛素分泌或胰岛素敏感性没有影响。相反，我完全通过选择性地将GE增加3倍来调节这一效应。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一个过程，即葡萄糖通过一种不依赖胰岛素的机制被吸收到外周组织中，然后代谢成乳酸，随后释放到循环中。在此背景下，我们提出了具体的目标1：确定FGF19是如何增加胰岛素非依赖性葡萄糖代谢的。这一目标的研究将1)量化这种大脑介导的葡萄糖摄取和代谢增加，以响应FGF19，2)确定它解释相关GE增加的程度，以及3)确定它发生在哪些组织中。这些目标将在小鼠身上使用从高血糖钳夹到代谢组学和生化分析等多种方法的组合来实现。类似的过程是否有助于减肥手术的抗糖尿病效果？啮齿动物的数据表明，大脑与减肥手术的降糖效果有关，在某些情况下，降糖涉及胰岛素非依赖和胰岛素依赖的机制。此外，减肥手术增加了胃肠道分泌的FGF19。基于这些考虑，我们提出了具体的目标2：确定增加的GE是否有助于减肥手术的抗糖尿病效果。这一目标的研究将 确定减肥手术是否激活了与FGF19类似的中枢神经系统机制，包括刺激胰岛素非依赖性葡萄糖摄取，然后转化为乳酸，然后乳酸释放到循环中。我们的研究发现，FGF19在大脑中的作用迅速、有效和选择性地增加胰岛素非依赖性的葡萄糖处置，确定了一种新的中枢神经系统驱动的机制，对人类糖尿病的发病机制和治疗具有翻译意义。这项提案中的研究试图澄清这种情况是如何发生的，以及它在多大程度上解释了减肥手术的抗糖尿病效果。

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.