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Human Molecular Genetics Advance Access published online on April 27, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl111
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© 2006 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received December 1, 2005
Revised April 1, 2006
Accepted April 17, 2006

Article

Obesity, Hyperphagia, and Increased Metabolic Efficiency in Pc1 Mutant Mice

David J. Lloyd 1, Sandy Bohan 2, and Nicholas Gekakis 2 *

1 Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins, Drive, La Jolla, CA 92121; Amgen, One Amgen Center Dr., Thousand Oaks, CA 91320
2 Genomics Institute of the Novartis Research Foundation, 10675 John Jay Hopkins, Drive, La Jolla, CA 92121

* To whom correspondence should be addressed.
Nicholas Gekakis, E-mail: ngekakis{at}gnf.org


  Abstract

Prohormone convertase 1 (PC1) mutations lead to obesity in humans. Pc1 knockout mice however, do not become obese; in fact they are runted due to a defect in growth-hormone releasing hormone (GHRH) 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 {alpha}-MSH. This is the first characterization of Pc1 mutation in a model organism that mimics human PC1 deficiency.


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