THE OB PROTEIN (LEPTIN) PATHWAY - A LINK BETWEEN ADIPOSE-TISSUE MASS AND CENTRAL NEURAL NETWORKS

OB protein (also known as leptin), a previously unknown protein signal , is secreted from adipose tissue, circulates in the blood, probably b ound to a family of binding proteins, and acts on central neural netwo rks that regulate ingestive behavior and energy balance. OB protein pr ovides a communication link from fat tissue and the brain. Rapidly acc umulating evidence suggests that OB protein appears to play a major ro le in the control of body fat stores through coordinated regulation of feeding behavior, metabolism, autonomic nervous system and body energ y balance in rodents, primates and humans. The field has rapidly moved from cloning of the ob gene to demonstration of complex regulation of ob gene expression in adipose tissue in rats and humans, and then the demonstration of potent biological activity of OB protein in ob/ob, d iet-induced, and lean mice as well as obese and lean rats but not in d b/db obese mice. A significant milestone was our demonstration that ce ntral administration of OB protein lead to reductions in food intake, body weight and alterations in metabolism consistent with activation o f the autonomic nervous system. These findings were followed by the id entification of a central binding site for labelled OB protein in the choroid plexus in ob/ob, db/db and lean mice as well as lean and obese Zucker rats. The expression cloning of a central receptor, OB-R, from the mouse choroid plexus soon followed. The OB-R receptor was found t o be expressed in the choroid plexus, the hypothalamus as well as seve ral peripheral tissues. OB-R exists in multiple forms; the two major f orms are a short form (with a truncated intracellular domain) and long form (with the complete intracellular domain). The long form is thoug ht to be the form that signals and mediates the biological effects of OB protein. Initial in situ hybridization studies have demonstrated th e mRNA for the long form OB-R receptor to be localized to the hypothal amus as well as peripheral sites. Recently, it was demonstrated that t he db gene encodes the OB-R receptor. Evidence has been provided for a specific transport system for OB protein to cross the blood-brain-bar rier and enter the brain of mice, rats and humans. The rate of transpo rt can be decreased by high plasma concentrations of OB protein. Thus, reduced entry of OB protein to the brain may be one of the mechanisms of reduced sensitivity of the OB protein pathway in obese individuals . OB protein appears to also play a role in the important neuroendocri ne adaptive responses to fasting and in the control of reproduction. T herapeutic approaches to the treatment of obesity based on OB protein ranging from OB protein by injection to OB-R receptor agonists and to upregulation of OB signalling pathways are under intense investigation .