Gastrointestinal peptides and mechanisms behind lipid infiltration

该NSERC发现补助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。这些肽是餐后由GI细胞释放到血液中的信号分子。我们最近报道，胃肠道肽酰化生长激素释放肽（AG）和胃动素，其天然同系物，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），产生增加脂肪酸（FA;脂肪）的摄取和储存，并减少其脂肪分解特性。我们先前已经观察到，添加AG减少培养的成熟L 6骨骼肌细胞中的葡萄糖转运。葡萄糖和脂肪酸在细胞表面有特定的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，并最终转化为肌肉收缩所需的能量底物。同时，脂肪在骨骼肌等组织中的浸润也会降低胰岛素的作用，损害肌肉功能。总之，这些结果表明，胃动素和AG不仅可以作用于脂肪细胞，而且还可以作用于其他代谢相关的细胞和组织，如骨骼肌细胞，以促进其向脂肪细胞的分化。然而，通过这些影响可以介导的机制和它们对肌肉生理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）调节成熟初级细胞能量底物摄取和储存的机制，（卫星）和永生化（L 6）培养的骨骼肌细胞; 2）未成熟骨骼肌的分化（卫星和L 6细胞）转化为“脂肪细胞样”表型; 3）这些肌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，这一新知识可以在许多显然不相关的领域中找到应用，例如预防人类肥胖和其他代谢紊乱，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.