Endocrine Abstracts

The regulatory processes of appetite and metabolism have turned out to be exceedingly complex and involve numerous hormones and neurotransmitters, particularly peptides. Evolutionary studies in our laboratory have shown that many genes encoding peptides and receptors were duplicated in the early stages of vertebrate evolution through chromosome duplications. Thus, many of the components have existed for 400–500 million years, for instance the various members of the families of NPY-like peptides, opioid peptides, tachykinins, glycoprotein hormone beta subunits (FSH, LH and TSH) and others. The chromosome duplications also explain the origin of many peptide receptors, for instance the NPY-family receptors, opioid receptors, oxytocin-vasopressin receptors, tachykinin receptors and CRF receptors. Also the glucocorticoid-mineralcorticoid receptors arose through a chromosome duplication. These observations of ancient chromosome duplications explain a great deal of the complexity of the vertebrate endocrine and neuronal networks. Duplication of complete genes in this manner means that the duplicates initially had identical gene regulation. This makes it particularly intriguing that some duplicates now have opposing functional roles. One striking example is the peptide hormone PYY, released from gut endocrine cells after meals, which acts as an appetite inhibitor on the Y2 receptor in the hypothalamus. In contrast, the related peptide NPY is the body’s most potent stimulator of appetite, acting on receptor subtypes Y1 and Y5. Probably the switch in function occurred when the duplicated genes became expressed in different cell types. We have functionally studied the roles of the NPY-family peptides in a herbivorous species with frequent meals, the guinea-pig, and a carnivore with rare meals, the dog. The role of NPY appears to be the same in the guinea pig as in intermittent feeders like rats. We are presently evaluating the role of PYY as an appetite inhibitor in dogs. Functional studies in different species will provide a firmer basis for predicting and testing the functions of these peptides in humans as well as their possible roles in states of obesity and anorexia.