Novel Anti-Diabetic Actions of Hypothalamic FGF19-FGFR1 Signaling

描述（由申请人提供）：葡萄糖刺激后，胰岛素依赖型和非依赖型机制都有助于恢复到基线血糖浓度。被称为葡萄糖有效性（GE）的胰岛素非依赖性成分与胰岛素一样对整体葡萄糖稳态起着重要作用，但它一直被视为一个固定且在很大程度上不受调节的过程，因此一直不是研究者的研究重点。然而，最近的几项观察结果提供了证据，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降低。此外，我们的初步数据显示，在瘦素缺乏的ob/ob小鼠中，脑室内注射抗糖尿病激素成纤维细胞生长因子-19 （FGF19）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，这种效应完全是通过选择性地增加3倍的GE来介导的。尽管这种影响的外周机制尚不清楚，但我们的数据强烈暗示了一个过程，即葡萄糖通过胰岛素不依赖的机制被外周组织吸收，随后代谢为乳酸盐，随后释放回循环中。在此背景下，我们提出了具体目标1：确定FGF19如何增加胰岛素不依赖型葡萄糖的处理。这方面的研究将1)量化脑介导的葡萄糖摄取和乳酸代谢的增加对FGF19的响应，2)确定其解释相关的GE增加的程度，3)确定其发生的组织。这些目标将在小鼠中实现，使用从高血糖钳制到代谢组学和生化分析的组合方法。是否类似的过程有助于减肥手术的抗糖尿病效果？啮齿动物的数据表明，大脑参与了减肥过程的降糖作用，在某些情况下，降糖涉及胰岛素非依赖型和胰岛素依赖型机制。此外，减肥过程增加了胃肠道中FGF19的分泌。基于这些考虑，我们提出了具体目标2：确定增加的GE是否有助于减肥手术的抗糖尿病效果。这方面的研究将会

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.