Role of ghrelin-derived peptides in the control of GH/IGF-1 axis, appetite and metabolism – ISO-GHRELIN

Although important progress have been made to characterize the factors involved in the regulation of appetite and metabolism, the mechanisms responsible for the pathophysiology of eating and metabolic disorders and the link between the neuroendocrine dysregulations occuring in these pathologies and nutrition are not well understood.
Amongst gastrointestinal factors known to modulate appetite and metabolism and maintain energy homeostasis, preproghrelin is a unique prohormone as it encodes several preproghrelin-derived peptides with structural and functional heterogeneity. Whereas the contribution of acyl ghrelin, the only orexigenic factor synthesized in the gastrointestinal tract and a powerful GH secretagogue, has been well characterized, the roles of the other variant desacyl ghrelin and the most recently identified obestatin, in these regulations remain unclear.
The absence of selective and reliable assays to selectively measure all three ghrelin-derived peptides (acyl ghrelin, desacyl ghrelin and obestatin) simultaneously in biological samples has been so far one limitation to understand how these key gastrointestinal peptides are regulated in physiological and pathological conditions.
The aim of this proposal is to decipher the relative importance played by a combination of these different peptides to modulate GH secretion, appetite and metabolism. The question will be adressed in three points.
(1) We propose to use selective and sensitive assays to determine the relative ratio of proghrelin-derived peptides in various nutritional conditions in rodents and in human eating disorders like anorexia nervosa or hyperphagia. We have indeed recently developed selective assays to reliably measure the different preproghrelin-derived peptides.
(2) To address directly the physiological importance of different proghrelin-derived peptides ratios in the control of GH/IGF-1 axis, appetite and metabolism, we will use preproghrelin deficient mice that lack all proghrelin-derived peptides and replace them with a combinations of proghrelin-derived peptides in a variety of dosages to mimic the ratios measured in physiological and pathological conditions.
(3) To understand the mechanisms of interaction of proghrelin-derived peptides in the central nervous system, we will explore cFos activity in genetically engineered mice expressing the Green Fluorescent Protein in specific subsets of neurons involved in the regulation of GH/IGF-1 axis and energy balance.
By combining biochemical and physiological approaches, this proposal will help to understand the combined actions of different gastrointestinal peptides derived from a unique prohormone, preproghrelin, within the central nervous system to maintain energy balance by regulating the activity of neuroendocrine circuits controlling the GH/IGF-1 axis, appetite and metabolism.