Ghrelin levels are elevated in PWS, but why, how, and whether it plays a role in hyperphagia or other aspects of PWS are all still unanswered questions. This project will explore if ghrelin plays a protective role in PWS with regards growth hormone deficiency, hypoglycemia and mental health issues, but a detrimental role with regards to extreme food-seeking behaviors and obesity. Clarifying the role of ghrelin is a critical step for future therapies designed to target the ghrelin system in PWS.
ABSTRACT: Plasma levels of the peptide hormone ghrelin are markedly elevated in individuals with Prader-Willi Syndrome (PWS), however the functional consequences of this elevation have not yet been determined. Many attribute the characteristic, maladaptive PWS eating behaviors directly to ghrelin, based mainly on ghrelin’s potent eating-stimulatory actions in non-PWS mouse models. Ghrelin’s abilities to promote growth hormone secretion, regulate blood glucose levels, lower depression and anxiety, and enhance survival may impact others of PWS’s characteristic features. Our overall goal in this proposal is to determine the “Why” of ghrelin elevation in PWS, with experiments designed to determine if the elevated ghrelin observed in PWS is beneficial, detrimental, or inconsequential. We hypothesize that ghrelin primarily serves a protective role in PWS – especially as it regards growth hormone deficiency-associated processes, hypoglycemia, mental health issues, and overall survival. The proposed studies will build upon preliminary data obtained during a 2015 year-long FPWR-funded project. Using genetically engineered mice and our expertise in ghrelin action, metabolism and mouse behavior, we plan to systematically probe the metabolic, growth and behavioral effects of elevated plasma ghrelin in PWS, with a focus on the neonatal period. Novel facets of this application include the use of recombinant DNA technology to disrupt the ghrelin system in a PWS mouse model and the concept that ghrelin has protective effects in PWS. Whatever its role, individuals with PWS deserve a full vetting of the impact of ghrelin on their condition. If our overall proposed hypothesis is proved, we hope to use these data for future translational studies that selectively target the ghrelin system in individuals with PWS.
Ghrelin Receptor Agonist Rescues Excess Neonatal Mortality in a Prader-Willi Syndrome Mouse Model. Rodriguez JA, Bruggeman EC, Mani BK, Osborne-Lawrence S, Lord CC, Roseman HF, Viroslav HL, Vijayaraghavan P, Metzger NP, Gupta D, Shankar K, Pietra C, Liu C, Zigman JM. Endocrinology. 159(12):4006-4022, 2018
Obesity Impairs the Action of the Neuroendocrine Ghrelin System. Zigman JM, Bouret SG, Andrews ZB. Trends Endocrinol Metab. 2016 Jan;27(1):54-63.
Jeffry Zigman, MD, PhD
University Texas Southwestern