WERTHEIMER AWARD AW0003 Ghrelin: discovery and physiological significance

Abstract

Energy balance is controlled by the intricate and precise interactions of substances to stimulate or suppress food intake and energy expenditure. The molecular mechanisms of energy balance are coming to light by the recent robust progresses in the molecular biology and neuroscience. In this regulation the bioactive peptides are recognized as the crucial molecules. In 1999, we discovered a novel growth hormone (GH)‐releasing peptide from rat stomach, and named it ‘ghrelin’. Ghrelin is a 28‐amino acid peptide with a marvelous structure modified by fatty acid, n‐octanoic acid. This n‐octanoyl modification at Ser‐3 is essential to its activity. Ghrelin is primarily produced in distinct endocrine cells, X/A‐like cells, in the stomach. Ghrelin‐producing neurons are also present in the hypothalamic arcuate nucleus, a region that regulates GH release and food intake. In fact, ghrelin stimulates GH release and feeding when administered centrally and peripherally. Ghrelin secretion is regulated under conditions of energy balance. Ghrelin is the first neuro‐enteric peptide that acts as a starvation‐signalling molecule in the periphery. The gastric vagal afferent is the major pathway conveying ghrelin's signals for starvation and GH secretion to the brain. Moreover, ghrelin has positive cardiovascular effects. Administration of ghrelin improves cardiac structure and function, and attenuates the development of cardiac cachexia in rats with heart failure. In humans, repeated administration of ghrelin improves left ventricular structure and function, exercise capacity, and muscle wasting in patients with chronic heart failure (CHF). These results suggest that ghrelin has cardiovascular protective effects and regulates energy metabolism through GH‐dependent and ‐independent mechanisms. Administration of ghrelin may be a new therapeutic approach for the treatment of CHF. Ghrelin also thus has multifaceted roles in the cardiovascular system and energy metabolism. Further studies of ghrelin will extend our understanding of how energy balance is controlled by the stomach.