The "yellow obese" mouse is another mutant strain that has been known for many years. Such mice develop adult-onset obesity, hyperinsulinemia, hyperglycemia, hyperphagia, and have a striking yellow color due to a mutation in the agouti gene. The agouti protein is normally synthesized in hair follicles and acts as a paracrine regulator or melanin synthesis, and hence coat color, by binding to and antagonizing the melanocortin-1 receptor (also known as the melanocyte stimulating hormone receptor). The yellow mutation results in constitutive expression of the agouti protein thoughout the body, which in the skin leads to yellow coat color.
Explaining how a mutation that affects coat color can also result in obesity requires some background on melanocortins and their receptors. Melanocortins are a group of pituitary peptide hormones that include adrenocorticotropin (ACTH) and the alpha, beta and gamma-melanocyte-stimulating hormones). Five melanocortin receptors have been identified to date, all of which are G-protein coupled receptors. It turns out the the agouti protein binds with high affinity not only to the melanocortin-4 receptor (expressed in skin), but also to the melanocortin-4 receptor, which is expressed in the brain, including in hypothalamic nuclei known to be involved in feeding behavior!
The research described above, along with several subsequent studies, led to recognition that melanocortin stimulation of certain hypothalamic neurons, via the melanocortin-4 receptor, inhibits feeding behavior. Two observations that strongly support this contention are that:
- targeted disruption of the melanocortin-4 receptor in mice leads to an obesity syndrome strikingly similar to that seen in the yellow obese mouse
- administration of melanocortin agonists into the cerebral ventricles of mice inhibits feeding in several models of hyperphagia, and coadministration of melanocortin antagonists (i.e. mimetics of the agouti protein) block this effect
In the yellow mouse, constitutive, ectopic production of agouti protein in the hypothalamus is thought to antagonize binding of melanocortins to the melanocortin-4 receptor, which perturbes feeding behavior. The melanocortin-4 receptor knockout mice show elevated levels of neuropeptide Y in certain areas of the hypothalamus, which would be predicted to result in hyperphagia and obesity. This effect is likely only part of the story of how melanocortins and their receptors contribute to regulation of body weight.