Chapter 3. Obesity: Leptin - Neuropeptide Y Interactions in the Control of Body Weight

Abstract

Recent advances in the biology of obesity have rekindled the interest of the pharmaceutical industry in this area. Among many factors perhaps the most important contributor is the cloning of the ob gene and discovery of its encoded gene product, leptin, an endocrine peptide that is secreted from the adipose tissue. Subsequently, it has been found that several other obese animals, such as the db/db mouse and Zucker rat, have defects in the gene encoding the leptin receptor. One of the important actions of this peptide is the suppression of the synthesis and release of neuropeptide Y (NPY). It is one of the most potent orexigenic agents and is the only endogenous neuropeptide that is capable of inducing obesity in experimental animals. Most animal models of obesity exhibit increased concentrations of hypothalamic NPY and messenger RNA (mRNA), encoding NPY. Therefore, it is presumed that leptin and NPY play important and interdependent roles in human obesity. This chapter discusses what appear to be two of the key components in the coordinate regulation of body weight, leptin, and NPY. Because leptin and NPY appear to be the key and interdependent players in the control of body weight, they are of primary interest for the development of pharmaceuticals. Mimicking the action of leptin is the most straightforward of the strategies and several pharmaceutical companies are developing leptin or leptin analogs for human use. Other strategies target the signaling pathway for leptin in an effort to increase leptin sensitivity. As NPY appears to be a key player in leptin signaling in the hypothalamus and hypothalamic NPY, concentrations are elevated in obese animals, specific receptor antagonists is likely to be an important strategy to understand the importance of this peptide and its interrelationships with leptin.