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Molecular and Cellular Biology, May 2005, p. 4189-4199, Vol. 25, No. 10
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.10.4189-4199.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Energy Homeostasis and Gastrointestinal Endocrine Differentiation Do Not Require the Anorectic Hormone Peptide YY

Susan Schonhoff,^1, Laurie Baggio,³ Christelle Ratineau,^1, Subir K. Ray,¹ Jill Lindner,⁴ Mark A. Magnuson,⁴ Daniel J. Drucker,³ and Andrew B. Leiter^1,2*

Division of Gastroenterology, GRASP Digestive Disease Center, Tufts New England Medical Center, Boston, Massachusetts,¹ Genetics Program, Tufts University School of Medicine, Boston, Massachusetts,² Department of Medicine, Toronto General Hospital, Banting and Best Diabetes Centre, University of Toronto, Toronto, Ontario, Canada,³ Department of Molecular Physiology and Biophysics, Vanderbilt University School of Medicine, Nashville, Tennessee⁴

Received 5 October 2004/ Returned for modification 9 December 2004/ Accepted 7 February 2005

The gastrointestinal hormone peptide YY is a potent inhibitor of food intake and is expressed early during differentiation of intestinal and pancreatic endocrine cells. In order to better understand the role of peptide YY in energy homeostasis and development, we created mice with a targeted deletion of the peptide YY gene. All intestinal and pancreatic endocrine cells developed normally in the absence of peptide YY with the exception of pancreatic polypeptide (PP) cells, indicating that peptide YY expression was not required for terminal differentiation. We used recombination-based cell lineage trace to determine if peptide YY cells were progenitors for gastrointestinal endocrine cells. Peptide YY⁺ cells gave rise to all L-type enteroendocrine cells and to islet and PP cells. In the pancreas, approximately 40% of pancreatic and rare ß cells arose from peptide YY⁺ cells, suggesting that most ß cells and surprisingly the majority of cells are not descendants of peptide YY⁺/glucagon-positive/insulin-positive cells that appear during early pancreagenesis. Despite the anorectic effects of exogenous peptide YY_3-36 following intraperitoneal administration, mice lacking peptide YY showed normal growth, food intake, energy expenditure, and responsiveness to peptide YY_3-36. These observations suggest that targeted disruption of the peptide YY gene does not perturb terminal endocrine cell differentiation or the control of food intake and energy homeostasis.

Present address: University of Massachusetts Biological Laboratories, Jamaica Plain, Mass.

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