Peptides, enzymes and obesity: New insights from a 'dead' enzyme

The identification of the fat mutation, which causes obesity in mice, as a defect in carboxypeptidase E (CPE) has raised more questions than answers. CPE is required for the processing of numerous neuroendocrine peptides and a mutation that inactivates CPE was predicted to be lethal. However, Cpe(fa t) mutated mice live and become obese. So, why are mice with the Cpe(fat) m utation viable, and why does obesity develop as a consequence of the pleiot ropic effects of this mutant allele? Recently, several new members of the c arboxypeptidase family have been discovered, of which at least one, CPD, ca n partially compensate by contributing to neuroendocrine pep tide processin g. Obesity due to the Cpe(fat) mutation is not caused by increased food con sumption but, rather, is a result of defective nutrient partitioning, the e xact mechanism of which remains to be elucidated.