Why do some people find it so hard to control the amount of food they eat? One idea is that this is caused by endogenous orexigen melanin-concentrating hormone (MCH) — a hormone that causes an increase in food intake. In Proceedings of the National Academy of Sciences, researchers confirm that MCH is an orexigen, and that the MCH receptor (MCH1R) is a physiologically relevent MCH receptor that is involved in energy homeostasis.

MCH is a hypothalamic neuropeptide that is derived from a larger pro-hormone precurser, PMCH, which also encodes other proteins, including the neuropeptides NEI and NGE. Pharmacological studies indicate that MCH is involved in energy homeostasis. In genetic experiments, mice that are deficient in Pmch are lean, hypophagic (eat less) and have an increased metabolic rate, whereas mice that overexpress Pmch are hyperphagic (eat more) and become slightly obese. Because these genetic manipulations of Pmch might affect the levels of NEI and NGE, further validation of MCH as an orexigen was required. MCH1R is highly selective for MCH, and is not activated by NEI or NGE. Mch1r-deficient mice were generated to evaluate the physiological function of MHC1R, and to determine the involvement of MCH in energy homeostasis.

Mch1r-deficient mice are lean with reduced fat mass compared with their wild-type litter mates. They also have altered neuroendocrine profiles; of particular note was the statistically significant increase in plasma corticosterone levels. Surprisingly, the mice are hyperphagic, and their leanness is a result of hyperactivity and altered metabolism. Whereas infusion of MCH induces hyperphagia and mild obesity in wild-type mice, it has no effect on Mhc1r-deficient mice, showing that MCHR1 is a physiologically relevent receptor in energy control.

Interestingly, although Mch1r and Pmch deficiencies result in the same lean phenotype, the underlying mechanisms are different. Mch1r-deficient mice are lean because of hyperactivity, whereas Pmch-deficient mice are lean because of hypophagia and increased metabolic rate. This observation indicates that other proteins that are encoded by Pmch contribute to the phenotype of the Pmch-deficient mice. It is not clear what causes the hyperactivity of the Mch1r-deficient mice, but as MCH1R is expressed in brain regions that are known to contain dopaminergic cell bodies and projections, dysregulation of dopaminergic signalling might have a role.

For the moment, the role of all the proteins that are encoded by PMCH is not fully understood, but it is clear that MCH and MCH1R have important functions in energy homeostasis. These studies validate MCH1R as a therapeutic target for obesity. Perhaps one day we'll all be able to walk by the dessert table without overindulging.