Novel Anti-Diabetic Actions of Hypothalamic FGF19-FGFR1 Signaling

下丘脑 FGF19-FGFR1 信号传导的新型抗糖尿病作用

• 批准号: 8673958
• 负责人: Michael W Schwartz
• 金额: $ 39.5万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8673958
• 关键词: Accounting; Animals; Anus; Back; Bariatrics; Biochemical; Blood Circulation; Blood Glucose; Brain; Canis familiaris; Collaborations; Data; Diabetes Mellitus; Effectiveness; FGFR1 gene; Fatty acid glycerol esters; Fibroblast Growth Factor; Fibroblast Growth Factor Receptors; Figs - dietary; Funding; Future; Gastrectomy; Gastric Bypass; Gastrointestinal tract structure; Glucose; Goals; Hepatic; Hormones; Human; Hyperglycemia; Hypothalamic structure; Infusion procedures; Injection of therapeutic agent; Insulin; Learning; Leptin; Leptin deficiency; Letters; Liver; Mammals; Mediating; Metabolism; Methods; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Operative Surgical Procedures; Pathogenesis; Perception; Peripheral; Plasma; Play; Procedures; Process; Rattus; Research; Research Personnel; Rodent; Rodent Model; Role; Sampling; Signal Transduction; Skeletal Muscle; Streptozocin; Testing; Tissues; Wild Type Mouse; Work; bariatric surgery; base; blood glucose regulation; diabetic; glucose disposal; glucose metabolism; glucose production; glucose tolerance; glucose uptake; improved; insulin secretion; insulin sensitivity; intravenous glucose tolerance test; metabolomics; novel; public health relevance; receptor; response

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.

描述（由申请人提供）：葡萄糖激发后，胰岛素依赖性和非胰岛素依赖性机制都有助于恢复到基线血糖浓度。胰岛素独立成分被称为葡萄糖有效性（GE），它对整体葡萄糖稳态的贡献与胰岛素一样大，但它被视为一个固定且基本上不受监管的过程，因此并未成为研究人员的研究重点。然而，最近的一些观察结果提供了大脑通过不依赖胰岛素​​的机​​制有效诱导血糖降低的能力的证据。我们的初步数据表明，在瘦素缺陷的 ob/ob 小鼠中，脑室内 (icv) 注射抗糖尿病激素成纤维细胞生长因子-19 (FGF19) 可以迅速使葡萄糖耐量正常化，尽管对胰岛素分泌没有影响或胰岛素敏感性。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。尽管这种效应背后的外周机制尚不清楚，但我们的数据强烈暗示葡萄糖通过独立于胰岛素的机​​制被外周组织吸收，随后代谢为乳酸，随后释放回循环中。在此背景下，我们提出具体目标 1：确定 FGF19 如何增加不依赖于胰岛素的葡萄糖处理。该目标的研究将 1) 量化 FGF19 引起的大脑介导的葡萄糖摄取和乳酸代谢增加，2) 确定其在多大程度上解释 GE 的相关增加，以及 3) 确定发生这种情况的组织。这些目标将通过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在小鼠中实现。 类似的过程是否有助于减肥手术的抗糖尿病作用？啮齿动物数据表明，大脑与减肥手术的降血糖作用有关，在某些情况下，降血糖涉及胰岛素依赖性和胰岛素依赖性机制。此外，减肥手术会增加胃肠道中 FGF19 的分泌。基于这些考虑，我们提出具体目标 2：确定 GE 增加是否有助于减肥手术的抗糖尿病作用。以此为目标的研究将 确定减肥手术是否激活类似于 FGF19 的 CNS 机制，包括刺激不依赖于胰岛素的葡萄糖摄取，然后转化为乳酸，然后释放到循环中。 我们发现 FGF19 在大脑中的作用快速、有效且选择性地增加不依赖于胰岛素的葡萄糖处理，这确定了一种新的、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转化意义。该提案中的研究旨在阐明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作用。