This Article Full Text Full Text (PDF) Supplemental Data Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jing, E. Articles by Good, D. J. Search for Related Content PubMed PubMed Citation Articles by Jing, E. Articles by Good, D. J.

Deletion of the Nhlh2 Transcription Factor Decreases the Levels of the Anorexigenic Peptides Melanocyte-Stimulating Hormone and Thyrotropin-Releasing Hormone and Implicates Prohormone Convertases I and II in Obesity

Department of Veterinary and Animal Sciences and Center for Neuroendocrine Studies (E.J., D.J.G.), University of Massachusetts, Amherst, Massachusetts 01003; and Division of Endocrinology, Department of Medicine (E.A.N., V.C.S., R.C.S.), Brown Medical School, Rhode Island Hospital, Providence, Rhode Island 02903

Address all correspondence and requests for reprints to: Dr. Deborah J. Good, Department of Veterinary and Animal Sciences, 304 Paige Laboratory, University of Massachusetts, Amherst, Massachusetts 01003. E-mail: goodd{at}vasci.umass.edu.

Body weight is controlled by the activation of signal transduction pathways in both the brain and peripheral tissues. Interestingly, although many hypothalamic neuropeptides and receptors have been implicated in the regulation of body weight, the transcriptional and posttranscriptional mechanisms through which these genes are expressed in response to changes in energy balance remain unclear. Our laboratory studies a mouse in which targeted deletion of the neuronal basic helix-loop-helix (bHLH) transcription factor, nescient helix-loop-helix 2 protein (Nhlh2), results in adult-onset obesity. The aim of this work was to use the phenotype of the Nhlh2 knockout mouse and the expression pattern of Nhlh2 to identify genes that are regulated by this transcription factor. In this article, we show that Nhlh2 is expressed throughout the adult hypothalamus. Using dual-label in situ hybridization, we demonstrate that, in the arcuate nucleus of the adult hypothalamus (ARC), Nhlh2 expression can be found in rostral proopiomelanocortin (POMC) neurons, whereas in the paraventricular nucleus (PVN), Nhlh2 is expressed in TRH neurons. In addition, we find that hypothalamic POMC-derived MSH in the ARC and TRH in the PVN are regulated posttranscriptionally via Nhlh2-mediated control of prohormone convertase I and II mRNA levels. This is the first report in which regulation of body weight is linked to the action of a neuronal bHLH transcription factor on prohormone convertase mRNA levels. Furthermore, this work supports a direct role for transcriptional control of neuropeptide processing enzymes in the etiology of adult-onset obesity.

This article has been cited by other articles:

				D. L. Fox and D. J. Good Nescient Helix-Loop-Helix 2 Interacts with Signal Transducer and Activator of Transcription 3 to Regulate Transcription of Prohormone Convertase 1/3 Mol. Endocrinol., June 1, 2008; 22(6): 1438 - 1448. [Abstract] [Full Text] [PDF]

				M. D. DeBoer, X. Zhu, P. R. Levasseur, A. Inui, Z. Hu, G. Han, W. E. Mitch, J. E. Taylor, H. A. Halem, J. Z. Dong, et al. Ghrelin Treatment of Chronic Kidney Disease: Improvements in Lean Body Mass and Cytokine Profile Endocrinology, February 1, 2008; 149(2): 827 - 835. [Abstract] [Full Text] [PDF]

				L. E. Pritchard and A. White Neuropeptide Processing and Its Impact on Melanocortin Pathways Endocrinology, September 1, 2007; 148(9): 4201 - 4207. [Abstract] [Full Text] [PDF]

				E. A. Nillni Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin Endocrinology, September 1, 2007; 148(9): 4191 - 4200. [Abstract] [Full Text] [PDF]

				X. Zhu, A. S. Gleiberman, and M. G. Rosenfeld Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks Physiol Rev, July 1, 2007; 87(3): 933 - 963. [Abstract] [Full Text] [PDF]

				D. J. Lloyd, S. Bohan, and N. Gekakis Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice Hum. Mol. Genet., June 1, 2006; 15(11): 1884 - 1893. [Abstract] [Full Text] [PDF]

				J. W. M. Creemers, L. E. Pritchard, A. Gyte, P. Le Rouzic, S. Meulemans, S. L. Wardlaw, X. Zhu, D. F. Steiner, N. Davies, D. Armstrong, et al. Agouti-Related Protein Is Posttranslationally Cleaved by Proprotein Convertase 1 to Generate Agouti-Related Protein (AGRP)83-132: Interaction between AGRP83-132 and Melanocortin Receptors Cannot Be Influenced by Syndecan-3 Endocrinology, April 1, 2006; 147(4): 1621 - 1631. [Abstract] [Full Text] [PDF]

				T. Zimmermann-Belsing and U. Feldt-Rasmussen Obesity: The New Worldwide Epidemic Threat to General Health and Our Complete Lack of Effective Treatment Endocrinology, April 1, 2004; 145(4): 1501 - 1502. [Full Text] [PDF]