Role of Ghrelin in the Pathophysiology of Eating Disorders
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Role of Ghrelin in the Pathophysiology of Eating Disorders Implications for Pharmacotherapy Sebastian Cardona Cano,1,2,3 Myrte Merkestein,4 Karolina P. Skibicka,5 Suzanne L. Dickson5 and Roger A.H. Adan1,3,4 1 2 3 4
Utrecht Research Group Eating Disorders, Utrecht, The Netherlands Parnassia Bavo Psychiatric Institute, The Hague, The Netherlands Rintveld Centre for Eating Disorders, Altrecht Mental Health Institute, Zeist, The Netherlands Department of Neuroscience and Pharmacology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, University of Utrecht, Utrecht, The Netherlands 5 Institute of Neuroscience and Physiology, The Sahlgrenska Academy at the University of Gothenburg, Gothenburg, Sweden
Abstract
Ghrelin is the only known circulating orexigenic hormone. It increases food intake by interacting with hypothalamic and brainstem circuits involved in energy balance, as well as reward-related brain areas. A heightened gutbrain ghrelin axis is an emerging feature of certain eating disorders such as anorexia nervosa and Prader-Willi syndrome. In common obesity, ghrelin levels are lowered, whereas post-meal ghrelin levels remain higher than in lean individuals. Agents that interfere with ghrelin signalling have therapeutic potential for eating disorders, including obesity. However, most of these drugs are only in the preclinical phase of development. Data obtained so far suggest that ghrelin agonists may have potential in the treatment of anorexia nervosa, while ghrelin antagonists seem promising for other eating disorders such as obesity and Prader-Willi syndrome. However, large clinical trials are needed to evaluate the efficacy and safety of these drugs.
1. Introduction Since its discovery in 1999,[1] ghrelin has emerged as an important gut-brain signal for appetite control and energy balance. It is a 28-amino acid peptide and the only known peripherally produced and centrally active orexigenic hormone. Ghrelin has been implicated in the pathophysiology of several diseases, including eating disorders and obesity. Thus, ghrelin agonists or antagonists may have therapeutic potential. In this review we focus
on evidence indicating a role for ghrelin in the pathophysiology of eating disorders and obesity and evaluate existing pharmacological evidence to determine the therapeutic potential of new ghrelinrelated drugs. 2. A Brief History of Ghrelin The discovery of ghrelin follows a rather unusual history, initiating in 1977 with the identification of the first member of a series of synthetic
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peptides (and later, non-peptides) that were derived from met-enkephalin and had potent growth hormone (GH)-releasing activity – the so-called ‘growth hormone secretagogues’ (GHS). The hexapeptide, GHRP-6,[2] now recognized as a ghrelin mimetic, received considerable attention due to its potent GH-releasing effects. Another GHS with improved biological availability after oral administration, named MK-06
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