Abstract
OB protein (also known as leptin), a previously unknown protein signal, is secreted
from adipose tissue, circulates in the blood, probably bound to a family of binding
proteins, and acts on central neural networks that regulate ingestive behavior and
energy balance. OB protein provides a communication link from fat tissue and the brain.
Rapidly accumulating evidence suggests that OB protein appears to play a major role
in the control of body fat stores through coordinated regulation of feeding behavior,
metabolism, autonomic nervous system and body energy 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, diet-induced, and lean mice as well as obese and lean rats but not in db/db obese mice. A significant milestone was our demonstration that central administration
of OB protein lead to reductions in food intake, body weight and alterations in metabolism
consistent with activation of the autonomic nervous system. These findings were followed
by the identification 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 to be expressed in the choroid plexus, the hypothalamus as well as several
peripheral tissues. GB-R exists in multiple forms; the two major forms are a short
form (with a truncated intracellular domain) and long form (with the complete intracellular
domain). The long form is thought to be the form that signals and mediates the biological
effects of OB protein. Initial in situ hybridization studies have demonstrated the
mRNA for the long form OB-R receptor to be localized to the hypothalamus as well as
peripheral sites. Recently, it was demonstrated that the db gene encodes the OB-R receptor. Evidence has been provided for a specific transport
system for OB protein to cross the blood-brain-barrier and enter the brain of mice,
rats and humans. The rate of transport 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 GB protein pathway in obese individuals. OB protein
appears to also play a role in the important neuroendocrine adaptive responses to
fasting and in the control of reproduction. Therapeutic approaches to the treatment
of obesity based on GB protein ranging from OB protein by injection to OB-R receptor
agonists and to upregulation of OB signalling pathways are under intense investigation.
Key words
ob Gene - OB-R Receptor - Obesity - Energy Balance - Feeding - Body Weight - Hypothalamus
- Obesity Genes
