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Melanin-Concentrating Hormone Receptor Is a Target of Leptin Action in the Mouse Brain

Joslin Diabetes Center and Harvard Medical School (E.G.K., N.A.T., J.W.M., E.M.-F.), Boston, Massachusetts 02215; and Eli Lilly & Co. Research Laboratories (L.S.), Indianapolis, Indiana 46285

Address all correspondence and requests for reprints to: Eleftheria Maratos-Flier, M.D., Joslin Diabetes Center, Room 620, One Joslin Place, Boston, Massachusetts 02215. E-mail: terry.maratos-flier{at}joslin.harvard edu.

Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that is important in the regulation of energy homeostasis. MCH signals via a seven-transmembrane G protein-coupled receptor, which is coupled to G_i. This receptor was initially cloned in rat and human and designated SLC-1 because of its homology to the somatostatin receptor. In rat brain, it is expressed in a pattern that mirrors the previously described pattern of projections of MCH-immunoreactive fibers.

In the present study we cloned the mouse MCH receptor (MCH-R) ortholog by a rapid amplification of 5'- and 3'-cDNA ends approach and have found it to be 98% homologous with the rat sequence. We have characterized MCH-R messenger RNA distribution in the mouse brain by in situ hybridization and have shown MCH-R to be expressed in diverse brain areas implicated in the regulation of feeding, body adiposity, and sensory integration of smell and gustatory inputs, including the hypothalamus [paraventricular nucleus (magnocellular part) and dorsomedial, ventromedial, and arcuate nucleus], areas of the olfactory pathway, and the nucleus of the solitary tract.

We also studied MCH-R regulation and found that MCH-R expression is increased 7-fold by 48-h fasting or genetic leptin deficiency (ob/ob mice) and is completely blunted by leptin administration. In contrast, MCH-R messenger RNA expression remains unaltered in genetic MCH deficiency. Our findings suggest that MCH-R constitutes a central target of leptin action in the mammalian brain.

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