Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway

CREB:TORC2 通路对肝糖异生的调节

基本信息

  • 批准号:
    8833274
  • 负责人:
  • 金额:
    $ 73.05万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-04-07 至 2019-02-28
  • 项目状态:
    已结题

项目摘要

Under fasting conditions, increases in circulating glucagon stimulate hepatic glucose production via induction of the cAMP pathway. Conversely, increases in gut-derived glucagon-like peptide 1 (GLP1) during feeding enhance glucose clearance by promoting insulin release. The transcription factor CREB is thought to mediate long term effects of both peptide hormones, following its phosphorylation by PKA and association with CBP/P300. The transcriptional response to cAMP follows burst-attenuation kinetics; CREB activity peaks after 1 hour of stimulation, returning to baseline after 4-6 hours. In addition to their effects on CREB phosphorylation, glucagon and GLP1 also increase CREB activity by stimulating its association with the cAMP Regulated Transcriptional Coactivators (CRTCs/TORCs), latent cytoplasmic CREB cofactors that translocate to the nucleus following their dephosphorylation in response to cAMP. CRTC1 is expressed only in brain, while CRTC2 and CRTC3 are co-expressed in most tissues. The extent to which CRTC2 and CRTC3 function on overlapping or distinct subsets of CREB target genes is unclear, however. In the previous grant period, we showed that the CREB/CRTC2 pathway contributes importantly to fasting glucose production; acute depletion of CRTC2 in liver substantially lowers blood glucose concentrations and gluconeogenic gene expression, while over-expression of wild-type and to a greater extent phosphorylation-defective CRTC2 increases gluconeogenesis. By contrast with effects of acute hepatic CRTC2 knockdown, mice with a whole-body knockout of CRTC2 show only modest reductions in fasting glucose levels; and they develop an insulin secretion defect as they age. These results point to the involvement of additional CREB coactivators that compensate for loss of CRTC2 in liver, and they suggest that CRTC2 expression in pancreatic islets also modulates circulating glucose concentrations through its effects on insulin secretion. Supporting the latter, MafA, a beta cell transcription factor that is required for insulin secretion, is strongly upregulated by CREB and CRTC2. Proposed studies during the upcoming grant period focus on the hypothesis that members of the CRTC family exert overlapping effects on CREB activity. The importance of a newly identified CREB interacting protein in potentiating CREB activity and compensating for loss of CRTC2 in CRTC2 mutant mice will be tested. Finally the role of a potent CREB inhibitor, which is upregulated in pancreatic islets under hyperglycemic conditions, in promoting resistance to Gs-coupled receptor signaling, will be evaluated. Three aims are proposed; they extend the previous work by addressing the mechanisms by which the CREB pathway promotes gluconeogenesis in liver and facilitates insulin secretion from pancreatic islets. In Aim 1, we will use mice with floxed alleles of CRTC2 and CRTC3 to evaluate the relative roles of these coactivators in modulating hepatic gluconeogenesis and insulin secretion. We will generate mice with tissue specific knockouts of CRTC2 and CRTC3 in liver or pancreatic islets. Do CRTC2 and CRTC3 exert overlapping effects on gluconeogenic gene expression in liver? Do they promote insulin secretion by upregulating the leucine zipper factor MafA? In Aim 2, we will test the role of BRD2-a bromodomain protein identified in a proteomic screen for CREB associated proteins- in stimulating expression of gluconeogenic genes. We will characterize domains in BRD2 and CREB that mediate this interaction; and the role of CREB acetylation in modulating the BRD2:CREB association will also be tested. We will evaluate whether inhibition of BRD2, through administration of a selective bromodomain inhibitor, improves glucose levels in the setting of insulin resistance. In Aim 3, we will examine the mechanism by which CREB target gene expression in pancreatic islets is down-regulated in insulin resistance. In particular, we will investigate the role of Protein Kinase Inhibitor beta (PKIB) in interfering with GLP1 and other hormones, following its upregulation in response to hyperglycemia: PKIB knockout mice will be used to determine whether depletion of this inhibitor improves pancreatic islet function in the setting of insulin resistance. Taken together, the proposed studies will provide new insight into mechanisms by which glucagon and GLP1 promote glucose balance through their effects on the CREB pathway in liver and pancreatic beta cells.
在禁食条件下,循环胰高血糖素的增加通过诱导cAMP途径刺激肝脏葡萄糖产生。相反,在进食期间肠源性胰高血糖素样肽1(GLP 1)的增加通过促进胰岛素释放来增强葡萄糖清除。转录因子CREB被认为介导两种肽激素的长期作用,随后通过PKA磷酸化并与CBP/P300结合。对cAMP的转录反应遵循爆发衰减动力学; CREB活性在刺激1小时后达到峰值,在4-6小时后返回基线。 除了对CREB磷酸化的影响外,胰高血糖素和GLP 1还通过刺激CREB与cAMP调节转录辅激活因子(CRTC/TORC)的结合来增加CREB活性,CRTC/TORC是潜在的细胞质CREB辅因子,在响应cAMP去磷酸化后易位至细胞核。CRTC 1仅在脑中表达,而CRTC 2和CRTC 3在大多数组织中共表达。然而,CRTC 2和CRTC 3在CREB靶基因的重叠或不同子集上发挥作用的程度尚不清楚。在之前的研究中,我们发现CREB/CRTC 2通路对空腹血糖的产生有重要作用;肝脏中CRTC 2的急性消耗大大降低了血糖浓度和促血管生成基因的表达,而野生型和磷酸化缺陷型CRTC 2的过度表达在更大程度上增加了促血管生成。 与急性肝脏CRTC 2敲除的效果相比,CRTC 2全身敲除的小鼠仅显示出空腹血糖水平的适度降低;随着年龄的增长,它们会出现胰岛素分泌缺陷。这些结果表明,参与额外的CREB辅激活剂,弥补肝脏中CRTC 2的损失,他们表明,CRTC 2在胰岛中的表达也通过其对胰岛素分泌的影响调节循环葡萄糖浓度。支持后者,MafA,胰岛素分泌所需的β细胞转录因子,被CREB和CRTC 2强烈上调。 在即将到来的资助期内,拟议的研究集中在CRTC家族成员对CREB活性产生重叠影响的假设上。将测试新鉴定的CREB相互作用蛋白在增强CREB活性和补偿CRTC 2突变小鼠中CRTC 2损失中的重要性。最后,将评估在高血糖条件下在胰岛中上调的有效CREB抑制剂在促进对GS偶联受体信号传导的抵抗中的作用。 提出了三个目标;他们通过阐明CREB途径促进肝脏中的胰岛生成和促进胰岛分泌胰岛素的机制,扩展了先前的工作。 在目标1中,我们将使用CRTC 2和CRTC 3的floxed等位基因的小鼠来评估这些基因的相对作用。 在调节肝硬化发生和胰岛素分泌中的辅活化剂。我们将产生肝脏或胰岛中CRTC 2和CRTC 3组织特异性敲除的小鼠。CRTC 2和CRTC 3对肝脏致瘤基因表达的影响是否重叠?它们是否通过上调亮氨酸拉链因子MafA促进胰岛素分泌? 在目标2中,我们将测试BRD 2-在CREB相关蛋白的蛋白质组学筛选中鉴定的溴结构域蛋白-在刺激致凋亡基因表达中的作用。我们将表征BRD 2和CREB中介导这种相互作用的结构域;还将测试CREB乙酰化在调节BRD 2:CREB关联中的作用。我们将评估通过施用选择性溴结构域抑制剂来抑制BRD 2是否改善胰岛素抵抗背景下的葡萄糖水平。 在目的3中,我们将研究CREB靶基因在胰岛中的表达在胰岛素抵抗中下调的机制。特别是,我们将研究蛋白激酶抑制剂β(PKIB)在干扰GLP 1和其他激素中的作用,在其响应高血糖的上调后:PKIB敲除小鼠将用于确定该抑制剂的消耗是否改善胰岛素抵抗背景下的胰岛功能。 总之,拟议的研究将为胰高血糖素和GLP 1通过其对肝脏和胰腺β细胞中CREB通路的影响促进葡萄糖平衡的机制提供新的见解。

项目成果

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MARC R MONTMINY其他文献

MARC R MONTMINY的其他文献

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{{ truncateString('MARC R MONTMINY', 18)}}的其他基金

Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway
CREB:TORC2 通路对肝糖异生的调节
  • 批准号:
    10359198
  • 财政年份:
    2019
  • 资助金额:
    $ 73.05万
  • 项目类别:
Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway
CREB:TORC2 通路对肝糖异生的调节
  • 批准号:
    8749897
  • 财政年份:
    2014
  • 资助金额:
    $ 73.05万
  • 项目类别:
Regulation of Hepatic Gluconeogenesis by the CREB:TORC2 Pathway
CREB:TORC2 通路对肝糖异生的调节
  • 批准号:
    9017999
  • 财政年份:
    2014
  • 资助金额:
    $ 73.05万
  • 项目类别:
Cross-talk between the circadian clock and the cAMP signaling pathway
生物钟和 cAMP 信号通路之间的串扰
  • 批准号:
    8087954
  • 财政年份:
    2011
  • 资助金额:
    $ 73.05万
  • 项目类别:
Cross-talk between the circadian clock and the cAMP signaling pathway
生物钟和 cAMP 信号通路之间的串扰
  • 批准号:
    8258301
  • 财政年份:
    2011
  • 资助金额:
    $ 73.05万
  • 项目类别:
Cross-talk between the circadian clock and the cAMP signaling pathway
生物钟和 cAMP 信号通路之间的串扰
  • 批准号:
    8449748
  • 财政年份:
    2011
  • 资助金额:
    $ 73.05万
  • 项目类别:
Cross-talk between the circadian clock and the cAMP signaling pathway
生物钟和 cAMP 信号通路之间的串扰
  • 批准号:
    8638961
  • 财政年份:
    2011
  • 资助金额:
    $ 73.05万
  • 项目类别:
DROSOPHILA TORC ASSOCIATED PROTEINS
果蝇 Torc 相关蛋白
  • 批准号:
    8171243
  • 财政年份:
    2010
  • 资助金额:
    $ 73.05万
  • 项目类别:
REGULATION OF BETA CELL GENES BY GLUCOSE AND INCRETINS
葡萄糖和肠促胰素对 β 细胞基因的调节
  • 批准号:
    8171328
  • 财政年份:
    2010
  • 资助金额:
    $ 73.05万
  • 项目类别:
CHARACTERIZATION OF THE DSIK3 PROTEIN
DSIK3 蛋白的表征
  • 批准号:
    8171465
  • 财政年份:
    2010
  • 资助金额:
    $ 73.05万
  • 项目类别:

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研究组蛋白乙酰化在基因组组织和白血病发生中的功能
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