Back
to the leptin mainpage*The agouti connection:
The story of the melanocortinë s link to the obesity actually began with a mutant mouse known as agouti, which has a genetic defect that endows the animals with bright yellow fur. (The name agouti is come from the banded pattern of the fur of the South American rodent.) They also have an obesity problem, as it does not show up until the late in life and is often accompanied by diabetes, particularly in males.
Researchers at Glaxo Wellcome cloned the agouti gene in 1992 and determined that its product is a 131 amino acid produced by hair follicles. At the time, however, they could not figure out what this protein had to do with the obesity. It was not until after Coneí s group cloned the first melanocortin receptor later that year. They had even inkling of how agouti could affect body weight.
The first melanocortin receptor (MCR-1) was found by Coneë s group located on the skin cell called melanocytes. A melanocortin known as (melanocyte stimulation hormone -MSH) binds to the receptor and signals the melanocytes to produce black pigment. Normally, the inhibition comes to cause yellow banding in the mouseë s fur. But in agouti mice are always turn on, the MCR-1 receptor is always blocked and their fur color is yellow instead of black. There might another function of the MCR in the brain, such as regulating weight and metabolism.
Two MCRs, MCR-3 and MCR-4, are produced in the arcuate nucleus of the hypothalamus, a prime target of leptin action as well as a seat of NPY production. After injected synthetic peptides mimicking melanocortin into the brains of both normal and ob mice, they found that he molecules bind to MCR-4 and suppress feeding, even the extra NPY is given to boost their appetites. Further evidence from Huszarë s team found that mice in which MCR-4 had been knocked out mimicked the weight gain and other symptoms of the agouti mice. They got a phenotype that mirrors the agouti effect. This finding put the neuron producing the melanocortin in to the major role in the body weight control and metabolism.
Thus, human obesity might be due to either overactivity of NPY pathway or too little activity in the melanocortin branch. The melanocortin loop is another way to screen drugs used in weight reducing therapies. Unlike leptin receptors, MCRs are also called G-protein coupled receptor, which traditionally are easily targets to be blocked with small molecule drugs. There are plenty opportunities in biotech and basic science researches lurking in the tangle of pathway still uncovered.