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

Abstract

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 α and rare β cells arose from peptide YY⁺ cells, suggesting that most β cells and surprisingly the majority of α 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.

ACKNOWLEDGMENTS

This work was supported in part by NIH grants DK43673, DK52870, and DK67166 to A.B.L. and the GRASP Digestive Disease Center grants P30-DK34928, T32-CA65441 and DK42502 to M.A.M. D. Drucker is supported by a Canada Research Chair in Regulatory Peptides, and the studies were supported in part by operating grants from the Canadian Institutes of Health Research. Use of the Transgenic/ES Cell Shared Resource was supported by DK20593.

We thank the staff of the Transgenic/ES Cell Shared Resource for their expert technical assistance.