Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice

Sainsbury, Amanda, Baldock, Paul A., Schwarzer, Christoph, Ueno, Naohiko, Enriquez, Ronaldo F., Couzens, Michelle, Inui, Akio, Herzog, Herbert and Gardiner, Edith M. (2003) Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice. Molecular and Cellular Biology, 23 15: 5225-5233. doi:10.1128/MCB.23.15.5225-5233.2003

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Author Sainsbury, Amanda
Baldock, Paul A.
Schwarzer, Christoph
Ueno, Naohiko
Enriquez, Ronaldo F.
Couzens, Michelle
Inui, Akio
Herzog, Herbert
Gardiner, Edith M.
Title Synergistic effects of Y2 and Y4 receptors on adiposity and bone mass revealed in double knockout mice
Journal name Molecular and Cellular Biology   Check publisher's open access policy
ISSN 0270-7306
Publication date 2003-08
Sub-type Article (original research)
DOI 10.1128/MCB.23.15.5225-5233.2003
Open Access Status File (Publisher version)
Volume 23
Issue 15
Start page 5225
End page 5233
Total pages 9
Place of publication Washington, DC, United States
Publisher American Society for Microbiology
Language eng
Abstract Neuropeptide Y regulates numerous physiological processes via at least five different Y receptors, but the specific roles of each receptor are still unclear. We previously demonstrated that Y2 receptor knockout results in a lean phenotype, increased cancellous bone volume, and an increase in plasma pancreatic polypeptide (PP), a ligand for Y4 receptors. PP-overexpressing mice are also known to have a lean phenotype. Deletion of the Y4 receptor also produced a lean phenotype and increased plasma PP levels. We therefore hypothesized that part of the Y2 phenotype results from increased PP action on Y4 receptors and tested this in PP transgenic Y4(-/-) and Y2(-/-) Y4(-/-) double knockout mice. Bone mass was not altered in Y4 knockout mice. Surprisingly, despite significant hyperphagia, Y2(-/-) Y4(-/-) mice retained a markedly lean phenotype, with reduced body weight, white adipose tissue mass, leptinemia, and insulinemia. Furthermore, bone volume was also increased threefold in Y2(-/-) Y4(-/-) mice, and this was associated with enhanced osteoblastic activity. These changes were more pronounced than those observed in Y2(-/-) mice, suggesting synergy between Y2 and Y4 receptor pathways. The lack of bone changes in PP transgenic mice suggests that PP alone is not responsible for the bone mass increases but might play a major role in the lean phenotype. However, a synergistic interaction between Y2 and Y4 pathways seems to regulate bone volume and adiposity and could have important implications for possible interventions in obesity and for anabolic treatment of osteoporotic bone loss.
Keyword Biochemistry & molecular biology
Cell biology
Dorsal vagal complex
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

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Created: Fri, 25 Jan 2008, 15:58:43 EST