Gastrointestinal peptides and mechanisms behind lipid infiltration

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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.