| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on March 6, 2006
Accepted on May 12, 2006
Departments of Genetics and Pediatrics, Stanford University School of Medicine, Stanford, CA 94305, USA, Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, Detroit, MI 48201, and Department of Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98104
* To whom correspondence should be addressed. E-mail: gbarsh{at}stanford.edu.
Energy homeostasis depends on the regulation of hypothalamic neurons by leptin, an adipocyte hormone whose circulating levels communicate body energy stores. Leptin activates the transcription factor Signal Transducer and Activator of Transcription 3 (Stat3) in hypothalamic neurons, including neuronal subtypes producing Agouti-related protein (Agrp), a neuropeptide which stimulates feeding. Previous studies have suggested a model in which high levels of Agrp transcription during fasting represent a "default" state that is actively repressed by phospho-Stat3 induced by leptin signaling in the fed state. We identify putative Stat3 binding elements in the Agrp promoter that have been highly conserved during vertebrate evolution. Using a reporter assay in transgenic mice that faithfully recapitulates normal regulation of Agrp, we show these sites are required, but in a way opposite to that predicted by the existing model: mutation of the sites leads to a default state characterized by a low level of Agrp transcription and insensitivity to fasting. We also find that removing activatable Stat3 from Agrp neurons has no detectable effect on steady-state levels of Agrp mRNA in the fed or fasted state. These results suggest a new model for transcriptional regulation of orexigenic neuropeptides in which the default level of expression is low in the fed state, and transcriptional activation in response to fasting is mediated by factors other than Stat3.
This article has been cited by other articles:
 |
|
 |
|
  L. Gong, F. Yao, K. Hockman, H. H. Heng, G. J. Morton, K. Takeda, S. Akira, M. J. Low, M. Rubinstein, and R. G. MacKenzie Signal Transducer and Activator of Transcription-3 Is Required in Hypothalamic Agouti-Related Protein/Neuropeptide Y Neurons for Normal Energy Homeostasis Endocrinology, July 1, 2008; 149(7): 3346 - 3354. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. van de Wall, R. Leshan, A. W. Xu, N. Balthasar, R. Coppari, S. M. Liu, Y. H. Jo, R. G. MacKenzie, D. B. Allison, N. J. Dun, et al. Collective and Individual Functions of Leptin Receptor Modulated Neurons Controlling Metabolism and Ingestion Endocrinology, April 1, 2008; 149(4): 1773 - 1785. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. L. Piper, E. K. Unger, M. G. Myers Jr., and A. W. Xu Specific Physiological Roles for Signal Transducer and Activator of Transcription 3 in Leptin Receptor-Expressing Neurons Mol. Endocrinol., March 1, 2008; 22(3): 751 - 759. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. W. Xu, L. Ste-Marie, C. B. Kaelin, and G. S. Barsh Inactivation of Signal Transducer and Activator of Transcription 3 in Proopiomelanocortin (Pomc) Neurons Causes Decreased Pomc Expression, Mild Obesity, and Defects in Compensatory Refeeding Endocrinology, January 1, 2007; 148(1): 72 - 80. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
