Human Molecular Genetics Advance Access originally published online on April 27, 2006
Human Molecular Genetics 2006 15(11):1884-1893; doi:10.1093/hmg/ddl111
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Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice
Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins Drive, La Jolla, CA 92121, USA
* To whom correspondence should be addressed. Tel: +1 8588121527; Fax: +1 8588121918; Email: ngekakis{at}gnf.org
Received December 1, 2005; Revised April 1, 2006; Accepted April 17, 2006
Prohormone convertase 1 (PC1) mutations lead to obesity in humans. However, Pc1 knockout mice do not become obese; in fact, they are runted due to a defect in growth-hormone releasing hormone processing, leading to the speculation that PC1 subserves different functions between mouse and human. Here, we report a novel allele of mouse Pc1 (N222D) that leads to obesity, abnormal proinsulin processing and multiple endocrinological defects. Increased energy intake and a more efficient metabolism contribute to the obesity in Pc1N222D/N222D mice. Defective proinsulin processing leads to glucose intolerance, but neither insulin resistance nor diabetes develop despite obesity. The obesity is associated with impaired autocatalytic activation of mature PC1 and reduced hypothalamic 
-MSH. This is the first characterization of Pc1 mutation in a model organism that mimics human PC1 deficiency.
Present address: Amgen, One Amgen Center Dr, Thousand Oaks, CA 91320, USA.
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