Obesity genes: molecular genetic approaches to drug target identification

The environment for developing novel therapeutic agents has undergone dramatic change over the past decade. Innovative strategies for identifying and utilizing molecular targets linked to particular human diseases are replacing the classic approach of screening chemical compounds for potential therapeutic action on unknown targets. Since genetic components are involved in many known diseases, mouse and human genetics, positional cloning and other molecular biology-based approaches are now used to identify genes that are associated with these diseases. It is thought that identification of these disease-linked genes may lead to the discovery and understanding of the physiologically relevant biochemical pathways underlying the disease processes. Clearly, a knowledge of these biochemical pathways will provide future molecular targets, enzymes or receptors, that will offer opportunities to apply modern methods of high throughput screening, medicinal chemistry, parallel synthesis and combinatorial chemistry for drug discovery. In this manuscript, we illustrate how mouse genetics and molecular biology-based approaches have led to the identification of all five known single gene mutations that cause obesity in mice. Additionally, we describe how identification of these genes has helped unravel underlying biochemical pathways that regulate behavioral, metabolic and neuroendocrine responses in rodents.