REDUCTION OF FOOD-INTAKE AND WEIGHT-GAIN BY THE OB PROTEIN REQUIRES ASPECIFIC SECONDARY STRUCTURE AND IS REVERSIBLE

Background: Obesity, the condition of excessive accumulation of fat is a poorly understood disorder and is a risk factor for type II diabete s, hypertension, and hyperlipidaemia. Recently, a putative mouse obese gene was cloned and its product, termed ob protein, was shown to be i nvolved in the regulation of body weight. Materials and Methods: Bacte rial and insect cells were used for expression of recombinant mouse ob protein. Amino-terminal sequence analysis and site-directed mutagenes is were used to identify and characterize the mature form of ob protei n. Genetically obese mice and wild-type rats were used to determine th e biological activity of ob protein. Results: Mouse ob protein is synt hesized as a precursor molecule, the mature form of which was found in mouse serum. Biochemical analysis identified the processing site in t he ob precursor molecule and an intramolecular disulfide bond in the m ature form that is necessary for activity. Reduction of food intake an d weight gain after administration of ob protein to genetically obese mice and wild-type rats is reversible. Discussion: This study demonstr ates that ob protein is a secreted satiety factor which regulates body weight and reduces food intake even in animals with no genetic body w eight abnormalities. The failure of ob protein to effect these paramet ers in db/db mice supports the hypothesis that these mice are deficien t in a signaling molecule that normally responds to the ob protein.