The
neuropeptide melanin-concentrating hormone (MCH) was originally isolated from the pituitary of salmon, in which it causes skin paling. MCH is also found abundantly in mammalian neurons, and has been detected in the lateral hypothalamus and zona incerta, brain regions that are at the center of feeding behavior. Acute central administration of MCH leads to a rapid and significant increase in food intake, while MCH expression changes in states of altered energy balance, such as fasting and
obesity. Furthermore, MCH knockout mice tend toward hypophagia and
leanness. In 1999, we and four other groups identified an orphan
G-protein-coupled receptor (GPCR) as a specific receptor for MCH (MCH-1 receptor). Although a second
MCH receptor (MCH-2 receptor) was isolated in humans, it was found to be non-functional or encode a non-functional pseudogene in non-human species, including rodents. The discovery of these
MCH receptors permitted the launch of a broad array of
drug screening efforts and three MCH-1 receptor antagonists were identified to reduce food intake and
body weight. Interestingly, some antagonists unexpectedly produced evidence that blockade of these receptors has
antidepressant and
anxiolytic activities. The expressions of the
MCH receptors, which have been implicated in regulating emotion, stress and motivation, make MCH an excellent candidate for integrating the various homeostatic stimuli necessary for maintaining the proper conditions of energy metabolism and other physiological functions. Finally, the speed at which
MCH receptor studies have been undertaken exemplifies the impact that this deorphanized GPCR will have on setting the stage for more detailed physiological studies.