The glucagon-like Peptide-2

Multiple peptide hormones produced within the gastrointestinal system act also in the central nervous system and aid in the regulation of energy homeostasis and metabolism. The list of these peptides is progressively increasing and includes glucagon-like peptide 2 (GLP-2) as an anorexigenic factor. GLP-2 is released from enteroendocrine L-cells following food intake and its principal target is represented by the gastrointestinal tract. GLP-2 has been shown to be an important intestinotrophic factor that stimulates epithelial cell proliferation and inhibits apoptosis. GLP-2 increases intestinal blood flow and the activity and expression of epithelial brush-border digestive enzymes and nutrient transporters, and consequently increases the intestinal digestive and absorptive capacity. It inhibits gastric and intestinal motility, thus providing another mechanism to increase absorption of nutrients. Current research has focused on determining its physiological actions and its biological mechanisms in the gut, while very little is known on the GLP-2 actions within the brain. This review provides an overview of the state of the art on GLP-2 biology. F. Mulè Dipartimento di Scienze e Tecnologie Molecolari e Biomolecolari (STEMBIO) Laboratorio di Fisiologia generale Università di Palermo Viale delle Scienze 90128 Palermo Italia Tel: 39 91 23897515 Fax: 39 91 6577501 Email: [email protected] Introduction In the last decades a wealth of data has expanded our knowledge on the glucagon-like peptide 2 (GLP-2) as important molecule involved in a wide variety of functions. GLP-2 was first discovered as an intestinotrofic factor in 1996, but today it is recognized as a pleiotropic hormone that exerts different actions, not only in the gastrointestinal tract but also in the central nervous system. Since the biological actions of GLP-2 converge at multiple levels on the regulation of nutrient assimilation and energy homeostasis, a great deal of interest has been generated for drug development with therapeutic potential. The aim of this review is to explore recent advances in our understanding of GLP-2 biology. Synthesis, secretion and degradation GLP-2 is a 33-amino-acid peptide, which is derived from the cleavage of proglucagon, a large prohormone that is mainly expressed in cells of the endocrine pancreas, in the enteroendocrine L-cells, most of which are located in the distal ileum and colon, in the brain. Alternative splicing of proglucagon through prohormone convertases leads to the tissuespecific release of GLP-2 and other peptides with diverse biological properties. In particular, in pancreatic alpha-cells proglucagon is cleaved by prohormone convertase (PC)-2 to form glucagon, the major glucagon fragment and intervening peptide (IP)1. In the gastrointestinal tract and in the brain, processing of proglucagon, which is operated by PC1/3, results in glucagon-like peptide-1 (GLP-1), GLP-2, IP2, oxynthomodulin and glicentin. GLP-2 is released in response to stimulation by luminal nutrient, including glucose, fatty acids and dietary fiber. After ingestion of nutrients, plasma levels of GLP2 increase 2to 5-fold, depending upon the size and nutrient composition of the meal. It has been supposed that the peptide diffuse across the subepithelial lamina propria to activate afferent nerves and/or to enter the circulation, thus it may act also as paracrine agent besides as endocrine hormone.