More than 70 years ago the glucostatic, lipostatic and aminostatic hypotheses proposed that the central nervous system sensed circulating levels of different metabolites, changing feeding behaviour in response to the levels of those molecules. In the last 20 years the rapid increase in obesity and associated pathologies in developed countries has involved a substantial increase in the knowledge of the physiological and molecular mechanisms regulating body mass. This effort has resulted in the

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... cent discovery of new peripheral signals, such as leptin and ghrelin, as well as new neuropeptides, such as orexins, involved in body-weight homeostasis. The present review summarises research into energy balance, starting from the original classical hypotheses proposing metabolite sensing, through peripheral tissue-brain interactions and coming full circle to the recently-discovered role of hypothalamic fatty acid synthase in feeding regulation. Understanding these molecular mechanisms will provide new pharmacological targets for the treatment of obesity and appetite disorders. Food intake regulation: Gastrointestinal signals: Adipose and pancreatic hormones: Neural control Abbreviations: AgRP, agouti-related peptide; ARC, arcuate nucleus of the hypothalamus; BBB, blood-brain barrier; CART, cocaine-and amphetamineregulated transcript; CCK, cholecystokinin; CB, cannabinoids; CNS, central nervous system; DMH, dorsomedial nucleus of the hypothalamus; EC, endocannabinoids; FAS, fatty acid synthase; GHS-R, growth hormone secretagogue receptor; GLP, glucagon-like peptide; NPY, neuropeptide Y; LHA, lateral hypothalamic area; MCH, melanin-concentrating hormone; MCnR, melanocortin receptor (n 1-5); NTS, nucleus of the solitary tract; OB-Ra-f, isoforms of leptin receptor; OX, orexin; OXM, oxyntomodulin; POMC, pro-opiomelanocortin; PP, pancreatic polypeptide; PVH, paraventricular nucleus of the hypothalamus; PYY, peptide YY; VMH, ventromedial nucleus of the hypothalamus.