Posttranslational processing of proghrelin and role of ghrelin and obestatin in the endocrine pancreas

Proghrelin is a protein synthesized by the stomach that when cleaved leads to two biologically active proteins called ghrelin and obestatin. Ghrelin, discovered in 1999 is one of the most powerful stimulants of food intake, while obestatin recently discovered in 2005, has an opposite effect i.e. inhibits food intake. Ghrelin also reduces the secretion of insulin, the hormone responsible for the regulation of glucose homeostasis. Mutations in preproghrlin gene were found to be linked to type 2 diabetes and obesity in human. Analysis of the proghrelin molecule structure reveals potential site of cleavage by specific enzymes called proprotein convertases. Our preliminary experiments reveal the expression of proghrelin and the receptor for the obestatin peptide in established pancreatic cell line secreting the pancreatic hormones insulin and glucagon. We propose to identify the mechanism leading to the cleavage of the large proghrelin molecule into small active ghrelin and obestatin. We also explore the functions of ghrelin and obestatin in the regulation of endocrine pancreas and therefore their role in the development of type 2 diabetes. The experiments proposed in this grant will help to clarify the mechanism underlying the processing of ghrelin/obestatin precursor into bioactive peptides. They will also establish the role of ghrelin and obestatin in the regulation of glucose homeostasis and therefore identify a new target for the treatment of type-2 diabetes