Mitochondrial dynamics in VMH neurons control glucose metabolism
Mitochondrial dynamics in VMH neurons control glucose metabolism
批准号:
10320602
负责人:
Sabrina Diano
金额:
$44.7万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-09-01 至 2023-05-31
中文摘要
为了了解代谢紊乱的病因,包括II型糖尿病,我们必须获得更好的治疗
英文摘要
To understand the etiology of metabolic disorders, including type II diabetes, it is essential that we gain better
insight into the neuronal circuitry related to glucose metabolism. VMH neurons control systemic glucose
metabolism via control of peripheral organs including the pancreas (insulin and glucagon). Glucose-excited
(GE) and glucose-inhibited (GI) neurons in the VMH have been identified as major players in the control of
peripheral glucose metabolism. While there is a consensus that both of these neuronal populations are involved
in systemic glucose metabolism, the cellular machinery that enables cells to be excited or inhibited by glucose
is unknown and how these 2 subpopulations of neurons, functioning synchronously, reach their target tissues is
ill-defined. Our proposal aims to address these long-lasting outstanding questions by identifying the
translational signature of VMH glucose sensing neurons in response to changes in glucose levels which
dictate their identity, as either GE or GI, and their target sites. Our published and ongoing studies supported
by the current funding period unmasked the crucial relevance of the intracellular mechanism involving
mitochondrial dynamics controlled by uncoupling protein 2 (UCP2) and dynamin-related protein 1 (DRP1) in
VMH response to glucose load and systemic control of glucose homeostasis. These results, together with our
data on the RNAseq of GE neurons unmasking genes relevant to lipid and glucose metabolism, and our results
showing that the activation of UCP2-dependent DRP1-mediated mitochondrial fission in VMH neurons is
associated with mitochondrial fatty acid oxidation, gave impetus to our hypothesis that a specific translational
signature in response to changes in glucose levels dictate the identity of the VMH glucose sensing
neurons whether they are GE or GI and their target sites and that glycolysis, and that lipid oxidation
drive GE neuronal activity enabled by mitochondrial fission. Our approach to these studies involves the
use of available genetically modified animal models that will allow us to combine innovative and state-of-the-art
techniques including RNAseq in neurons while activated, genetic and viral targeting, CRISPR/Cas9, the iDISCO
technique, together with the confocal- and electron microscopic examinations.
The completion of these studies will give new insights in the central regulation of glucose metabolism.
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会议论文
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Mitochondrial dynamics in VMH neurons control glucose metabolism
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Mitochondrial dynamics in VMH neurons control glucose metabolism
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