NPY-Ergic agents for the treatment of obesity

Obesity is one of the most challenging clinical conditions in Western societies, affecting one-third of the US population. Energy homeostasis is maintained by complex and multifaceted processes that are regulated by the central nervous system. The hypothalamus is one of the main brain regions responsible for maintaining energy homeostasis in the body. Neuropeptide Y (NPY), a 36 amino acid linear peptide, is one of the most abundant neuropeptides expressed and released in nuclei of the hypothalamus. NPY is also the most potent orexigenic agent known to man. It exerts its action on enhancement of food intake and reduction of energy expenditure via G-protein-coupled NPY receptors. There are six known and five cloned NPY receptors, two of which, the Y1 and Y5 receptors, are implicated in regulating appetite and food intake. Whereas genetic studies provide confounding evidence for the involvement of these receptors in energy homeostasis, pharmacological studies indicate that both the Y1 and the Y5 receptors mediate NPY’s effect on food intake in rodents. This review summarizes the role of NPY in energy homeostasis, the reported evidence for the involvement of different receptors in NPY’s action, and the advancement of pharmacological tools for these receptors which might lead us to useful treatments of human obesity. Drug Dev. Res. 51:94–111, 2000.