ABSTRACT
Homeostatic control of energy balance is a key biological function essential for the survival of individuals and species. Maintenance of the energy status of an organism critically relies on the dynamic balance between energy expenditure and food intake. In this equation, expression of appetite (dened as the motivational drive toward an energy source) appears as a pivotal, highly regulated phenomenon, based on the complex physiological interaction of afferent signals (which promote or inhibit appetite) and effector mechanisms (which restrain or get into motion the drive toward food intake). Among the former, multiple peripheral factors, arising mostly from the adipose tissue, the pancreas, and the gastrointestinal tract, have been identied in the last decades as powerful regulators of central circuits at the hypothalamus, as well as in the brain stem and limbic system. At those sites, such factors actively modulate neuropeptide release and, thereby, participate in the control of food intake and energy expenditure.1,2
In this context, leptin is probably the most illustrative paradigm of peripheral regulator of energy balance. Leptin was originally identied in 1994 as a secreted hormone, primarily produced in the white adipose tissue, displaying a very potent satiating activity. Interestingly, circulating leptin levels were demonstrated to directly correlate with the amount of adiposity. Therefore, leptin appeared to serve an essential function in signaling the amount of body energy stores to the hypothalamic centers controlling food intake, thus contributing to body weight homeostasis.3,4 Indeed, a wealth of experimental and epidemiological evidence, gathered in the last decade, has fully conrmed the crucial role of leptin in the control of metabolism and energy balance. Moreover, identication of
Introduction .................................................................................................................................... 161 Discovery of Ghrelin ...................................................................................................................... 162 Structure of Ghrelin and Its Functional Receptor, the GHS-R ...................................................... 162 Distribution and Biological Functions of Ghrelin: An Overview .................................................. 163 Ghrelin and the Control of Appetite: Major Effects and Mechanisms of Action .......................... 164 Regulation of Ghrelin Levels and Interaction with Leptin System ................................................ 165 Ghrelin as Neuroendocrine Integrator Linking Energy Status and Other Key Functions ............. 166 Major Conclusions and Future Perspectives .................................................................................. 167 Acknowledgments .......................................................................................................................... 168 References ...................................................................................................................................... 168
leptin in the mid-1990s, coinciding with the exponential increase in the prevalence of obesity and other weight disorders, boosted an extraordinary activity, in terms of basic and clinical research, aimed at identifying the molecular and physiological basis for the dynamic regulation of body weight. This research activity has not only helped to characterize the physiology of leptin but has also signicantly contributed to enlarge our knowledge on the molecules and networks involved in the dynamic control of food intake. One of these molecules turned out to be the gut-derived hormone, ghrelin.
