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Reduction of food intake and weight gain by the ob protein requires a specific secondary structure and is reversible
1Department of Chiron Technologies, Chiron Corporation, Emeryville, California 94608, USA.
Background:
Obesity, the condition of excessive accumulation of fat is a poorly understood disorder and is a risk factor for type II diabetes, hypertension, and hyperlipidaemia. Recently, a putative mouse obese gene was cloned and its product, termed ob protein, was shown to be involved in the regulation of body weight.
Materials And Methods:
Bacterial and insect cells were used for expression of recombinant mouse ob protein. Amino-terminal sequence analysis and site-directed mutagenesis were used to identify and characterize the mature form of ob protein. Genetically obese mice and wild-type rats were used to determine the biological activity of ob protein.
Results:
Mouse ob protein is synthesized as a precursor molecule, the mature form of which was found in mouse serum. Biochemical analysis identified the processing site in the ob precursor molecule and an intramolecular disulfide bond in the mature form that is necessary for activity. Reduction of food intake and weight gain after administration of ob protein to genetically obese mice and wild-type rats is reversible.
Discussion:
This study demonstrates that ob protein is a secreted satiety factor which regulates body weight and reduces food intake even in animals with no genetic body weight abnormalities. The failure of ob protein to effect these parameters in db/db mice supports the hypothesis that these mice are deficient in a signaling molecule that normally responds to the ob protein.
Insights
Obesity is a complex disorder. This study shows that the ob protein acts as a secreted satiety factor, regulating body weight and reducing food intake in mice and rats.
Area of Science:
- Molecular biology
- Endocrinology
- Genetics
Background:
- Obesity is a poorly understood disorder and a risk factor for type II diabetes, hypertension, and hyperlipidaemia.
- The mouse obese gene (ob) and its product, ob protein, have been identified as key players in body weight regulation.
Purpose of the Study:
- To characterize the mature form of the ob protein and determine its biological activity.
- To investigate the role of ob protein in regulating body weight and food intake.
Main Methods:
- Recombinant mouse ob protein expression in bacterial and insect cells.
- Amino-terminal sequence analysis and site-directed mutagenesis for protein characterization.
- Administration of ob protein to genetically obese mice and wild-type rats to assess biological activity.
Main Results:
- Mouse ob protein is synthesized as a precursor, with the mature form detected in serum.
- An intramolecular disulfide bond in the mature ob protein is crucial for its activity.
- Administration of ob protein reversibly reduced food intake and weight gain in obese mice and normal rats.
Conclusions:
- Ob protein functions as a secreted satiety factor, regulating body weight and decreasing food intake.
- The ineffectiveness of ob protein in db/db mice suggests a deficiency in a downstream signaling molecule.