Gastrointestinal peptides and mechanisms behind lipid infiltration

NSERC发现基金旨在支持一项基础研究计划，该计划旨在建立特定胃肠道(GI)多肽的作用与能量平衡调节机制之间的关系。这些多肽是信号分子，在进餐后由胃肠道细胞释放到血液中。我们最近报道，胃肠激素酰化生长素(AG)及其天然同系物胃动素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)，增加脂肪酸(FA；脂肪)的摄取和储存，并降低其脂解特性。我们之前已经观察到，添加AG会减少培养的成熟L6骨骼肌细胞中的葡萄糖转运。在表面有特定胰岛素受体的细胞中，葡萄糖和脂肪酸被转化为能量。结合胰岛素促进葡萄糖和脂肪酸进入肌肉细胞，最终将转化为肌肉收缩所需的能量底物。研究还表明，骨骼肌等组织中的脂质渗透可能会降低胰岛素的作用，并损害肌肉功能。综上所述，这些结果表明，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，这些效应的调节机制以及它们与肌肉生理学的相关性仍有待阐明。因此，我们想要探讨胃动素和AG对以下方面的影响：1)成熟的原代(卫星)和永生化(L6)培养的骨骼肌细胞摄取和储存能量底物的调控机制；2)未成熟骨骼肌(卫星和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；4)这些骨骼肌细胞的类型和收缩能力。最终，这一新知识可能会在许多看似无关的领域找到应用，例如预防人类肥胖和其他代谢紊乱，以及开发新的方法来提高运动成绩或农业中的肉类生产。

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.