LONDON - The prospects that we may one day have a drug to treat obesity have improved with the identification of the receptor for a molecule known to play a key role in feeding and appetite control.
Scientists working at SmithKline Beecham in Harlow, Essex, have discovered the identity of the receptor for melanin-concentrating hormone (MCH), a molecule that stimulates feeding when injected into rats' brains.
The group reported its findings in a July 15 letter to Nature, titled, "Melanin-concentrating hormone is the cognate ligand for the orphan G-protein-coupled receptor SLC-1."
Jonathon Chambers, a research scientist at SmithKline Beecham and one of the authors of the letter, said, "Finding this receptor is like finding a lock to the door of obesity. If we could prevent MCH from binding to the receptor - seal up the lock, so the key can't enter - then it would be a major step forward in the fight against obesity."
Shelagh Wilson, associate director of vascular biology at SmithKline Beecham and one of the authors of the Nature letter, told BioWorld International: "We are very excited by the discovery of this potential new target for treating obesity. We are currently trying to design drugs that will antagonize the effects of MCH at this receptor, and these clearly may be potential drugs for treating obesity. But there is a long way to go yet. It will be a year or so before we can begin testing compounds in animals, and new drugs can of course take 10 years or more to reach the market."
The discovery stems, Wilson indicated, from SmithKline Beecham's decision several years ago to invest in genomics research. This approach has involved taking sequences from the human genome, trying to find out their function and whether they are involved in disease and, if they are, whether it is possible to design drugs targeting the sequences to treat those diseases.
As part of this process, researchers at SmithKline Beecham in Harlow and in King of Prussia, Pa., were screening a complementary DNA library for genes when they cloned a gene encoding a protein of 353 amino acids. This turned out to be a G-protein-coupled receptor known as SLC-1.
This receptor - known as an "orphan receptor" because no one knew which protein or peptide it responded to - belongs to a family of cell surface molecules that transmit extracellular signals to the interior of the cell.
The scientists took the gene for this receptor and expressed it in a cell line, which was then used to screen a library of peptides. MCH was the only substance among these peptides to cause a rise in intracellular calcium in the transfected cells - a measure of intracellular signaling in response to receptor stimulation.
Other experiments showed that peptides related to MCH had no such effect, and that MCH had very high affinity for SLC-1.
Studies to find out the distribution of SLC-1 in the brains of rats showed this receptor was mainly found in the cell bodies of the ventromedial and dorsomedial nuclei of the hypothalamus. Wilson added: "These are exactly the regions of the brain that are well known to be involved in modulating food intake."
MCH was first discovered in teleost fish. In these animals, it lightens skin pigment cells, while a-melanocyte stimulating hormone (a-MSH) darkens them. In their letter to Nature, the team wrote: "In mammals, the effects of these peptides on skin pigmentation have been lost, but their mutually antagonistic relationship has been maintained in other physiological roles such as feeding." Thus, MCH stimulates food intake while a-MSH suppresses appetite. Other experiments support the theory that these two molecules act at separate receptors.
Wilson concluded: "The fact that MCH and a-MSH appear to have different receptors reflects that there are many pathways by which food intake can be regulated. This new finding gives us another pathway by which we can try to modulate food intake. It's too soon to say, but SLC-1 may just be the factor that tips the balance and gives us a good anti-obesity drug."