Gastrointestinal peptides and mechanisms behind lipid infiltration

这项NSERC发现基金旨在支持一项基础研究计划，旨在建立特定胃肠道（GI）肽的作用与能量平衡调节机制之间的关系。这些多肽是一种信号分子，在用餐后由胃肠道细胞释放到血液中。我们最近报道了GI肽酰化的胃饥饿素（AG）和胃动素（其天然同源物）可以诱导成纤维细胞样细胞分化为成熟的脂肪细胞（脂肪细胞），从而增加脂肪酸（FA；脂肪）的摄取和储存，并降低其脂解特性。我们之前观察到，添加AG可以减少培养的成熟L6骨骼肌细胞的葡萄糖转运。葡萄糖和FA在细胞表面有特定胰岛素受体的细胞中转化为能量。结合胰岛素促进葡萄糖和FA进入肌肉细胞，最终转化为肌肉收缩所需的能量底物。此外，骨骼肌等组织中的脂质浸润也可能降低胰岛素的作用，损害肌肉功能。综上所述，胃动素和AG不仅可以作用于脂肪细胞，还可以作用于其他代谢相关的细胞和组织，如骨骼肌细胞，促进其向脂肪细胞分化。然而，这些作用的介导机制及其与肌肉生理学的相关性仍有待阐明。因此，我们希望探讨胃动素和AG处理对以下方面的影响：1)调节成熟原代（卫星）和永生化（L6）培养骨骼肌细胞对能量底物的吸收和储存的机制；2)未成熟骨骼肌（卫星细胞和L6细胞）分化为“脂肪细胞样”表型；3)这些肌肉细胞的线粒体特性和4)这些骨骼肌细胞的类型和收缩能力。最终，这种新知识可以应用于许多看似不相关的领域，比如预防肥胖和人类其他代谢紊乱，以及开发改善运动表现或农业肉类生产的新方法。

This NSERC Discovery Grant is intended to support a fundamental research program aiming to establish a relationship between the action of specific gastrointestinal (GI) peptides and mechanisms underlying the regulation of energy balance. These peptides are signal molecules that are released into the blood by GI cells following a meal. We have recently reported that GI peptides acylated ghrelin (AG) and motilin, its natural homolog, could induce fibroblast-like cells to differentiate into mature adipocytes (fat cells), yielding to an increase of fatty acid (FA; fat) uptake and storage and a reduction of their lipolytic properties. We had observed previously that adding AG reduces glucose transport in cultured mature L6 skeletal muscle cells. Glucose and FA are converted to energy in cells that have specific insulin receptors on their surface. Bound insulin facilitates glucose and FA entry in muscle cells and will ultimately be converted into energy substrates required for muscle contraction. It also appears that lipid infiltration in tissues such as skeletal muscle could reduce insulin's effect and impair muscular functions as well. Taken together, these results indicate that motilin and AG could not only act on adipocytes but also on other metabolically-relevant cells and tissues such as skeletal muscle cells, to promote their differentiation into adipocytes. However, mechanisms through which these effects could be mediated and their relevance on muscle physiology remain to be elucidated. Therefore, we want to explore the effects of motilin and AG treatments on: 1) the mechanisms regulating energetic substrate uptake and storage in mature primary (satellite) and immortalized (L6) cultured skeletal muscle cells; 2) the differentiation of immature skeletal muscle (satellite and L6 cells) into an "adipocyte-like" phenotype; 3) mitochondrial properties of these muscle cells and 4) the typology and contraction capacity of those skeletal muscle cells. Ultimately, this new knowledge could find applications in a host of apparently unrelated areas such as the prevention of obesity and other metabolic disorders in man, as well as the development of novel approaches for improvement of athletic performance or meat production in agriculture.