Ghrelin Antagonists: A Potential Therapy for Obesity, Diabetes, Behavioral and Eating Disorders

Organizers: John R. Zysk, PhD, AstraZeneca Pharmaceuticals and Brian J. Murphy, PhD, Bristol-Myers Squibb Company

The role of the gut peptide hormone ghrelin as an appetite enhancer and an anabolic regulator, places it as a potential target for the treatment of obesity and other metabolic disorders. Moreover, abnormal levels of ghrelin have been associated with both anorexia and bulimia nervosa. Because emotional changes can affect feeding behavior, ghrelin has also been of recent interest in the area of psychiatric disorders. These potential effects by ghrelin on metabolism and behavior suggest that antagonists of this hormone may provide therapy for several important conditions challenging health care in this and other countries. This symposium will focus on the rationale, strategies, feasibility and risks involved in the use of ghrelin antagonists as a potential therapeutic path toward the treatment of these diseases.

Program: 1:00-1:15 PM: Introduction and Symposium Theme
John Zysk, PhD, AstraZeneca
Brian J. Murphy, PhD, Bristol-Myers Squibb Company

1:15-2:00 PM:
Jeffrey M. Zigman, MD, PhD, University of Texas Southwestern Medical Center
Ghrelin Overview

2:00-2:45 PM:
Michael O. Thorner, MBBS, DSc, University of Virginia
Ghrelin Acylation and Secretion are Regulated Independently and Act to Modulate Growth Hormone Secretion

2:45-3:05 PM: Coffee Break

3:05-3:50 PM:
Matthias Tschoep, MD, University of Cincinnati
Ghrelin Controls Energy and Lipid Metabolism

3:50-4:35 PM:
Sabrina Diano, PhD, Yale University School of Medicine
The Relationship of Ghrelin to Appetite Regulation, Memory and Anxiety Behavior

4:35-5:20 PM:
Roy G. Smith, PhD, Baylor College of Medicine
Ghrelin Pharmacology

5:20-5:30 PM: Wrap-up/Discussion

Abstracts

Ghrelin Overview
Jeffrey M. Zigman, MD, PhD, University of Texas Southwestern Medical Center

The purpose of my presentation is to provide a broad overview of all things ghrelin. I will touch on some of the current controversies in the field including the relevance of intact ghrelin signaling pathways to body weight homeostasis, the source of ghrelin in the brain, and the activity of non-acylated ghrelin. In addition, I will discuss some of our new findings regarding the roles of ghrelin in mood and anxiety.

Ghrelin Acylation and Secretion are Regulated Independently and Act to Modulate Growth Hormone Secretion
Michael Thorner, MBBS, DSc, University of Virginia

Ghrelin, an acylated peptide hormone secreted from the gut, regulates appetite and metabolism. Discovered as an endogenous ligand of the growth hormone (GH) secretagogue receptor, ghrelin's role in GH regulation remains unclear. Eight young men were studied on fed and long-term (61.5 h) fasting admissions. Full-length acyl- and des-acyl ghrelin were measured separately using newly developed specific two-site ELISAs. Acyl-ghrelin, des-acyl ghrelin, GH, insulin and cortisol were measured every 10 min for 26.5 h. On the fed admission, acyl- and des-acyl ghrelin showed similar dynamics; both were inhibited by meals and increased at night. During fasting, acyl-ghrelin decreased significantly, but total ghrelin levels remained unchanged. During fed admissions significant correlations between acyl-ghrelin levels and the size of proximal GH pulses were observed and mathematical modeling of ghrelin regulation by insulin and cortisol explained 51.0% of the variance in acyl- and 50.5%