This Article Full Text Full Text (PDF) 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 Münzberg, H. Articles by Bjørbæk, C. Search for Related Content PubMed PubMed Citation Articles by Münzberg, H. Articles by Bjørbæk, C.

Role of Signal Transducer and Activator of Transcription 3 in Regulation of Hypothalamic Proopiomelanocortin Gene Expression by Leptin

Department of Medicine, Division of Endocrinology (H.M., L.H., A.N.H., C.B.), Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215; and Division of Endocrinology, Department of Medicine (E.A.N.), Brown Medical School, Rhode Island Hospital, Providence, Rhode Island 02903

Address all correspondence and requests for reprints to: Dr. Christian Bjørbæk, Division of Endocrinology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, Massachusetts 02215. E-mail: cbjorbae{at}caregroup.harvard.edu.

Leptin acts on the brain to regulate body weight and neuroendocrine function. Proopiomelanocortin (POMC) neurons in the hypothalamus are important targets of leptin. These cells express the leptin receptor ObRb, and leptin can regulate POMC mRNA levels, but the cellular mechanisms by which this occurs is unknown. Here we show evidence that leptin stimulates pomc gene transcription via activation of intracellular signal transducer and activator of transcription 3 (STAT3) proteins. In pomc-promoter assays using transfected cells, leptin induces pomc promoter activity. Expression of dominant negative STAT3 strongly suppresses this effect. Furthermore, maximal activation requires the presence of the STAT3-binding site, tyrosine 1138, of ObRb. Mutational analysis identifies a 30-bp promoter element that is required for regulation by leptin. In rats, robust leptin-dependent induction of STAT3 phosphorylation is demonstrated in hypothalamic POMC neurons using double immunohistochemistry. In total, approximately 37% of POMC cells are positive for phospho-STAT3 after leptin treatment. Furthermore, leptin-responsive POMC neurons are concentrated in the rostral region of the hypothalamus. Combined, our data show that a subpopulation of POMC neurons is leptin-responsive and suggest that stimulation of hypothalamic pomc gene expression in these cells requires STAT3 activation. We speculate that STAT3 is critical for leptin-dependent effects on energy homeostasis that are mediated by the central melanocortin system.

This article has been cited by other articles:

				E. Isganaitis, J. Jimenez-Chillaron, M. Woo, A. Chow, J. DeCoste, M. Vokes, M. Liu, S. Kasif, A.-M. Zavacki, R. L. Leshan, et al. Accelerated Postnatal Growth Increases Lipogenic Gene Expression and Adipocyte Size in Low-Birth Weight Mice Diabetes, May 1, 2009; 58(5): 1192 - 1200. [Abstract] [Full Text] [PDF]

				T. Babic, R. L. Townsend, L. M. Patterson, G. M. Sutton, H. Zheng, and H.-R. Berthoud Phenotype of neurons in the nucleus of the solitary tract that express CCK-induced activation of the ERK signaling pathway Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2009; 296(4): R845 - R854. [Abstract] [Full Text] [PDF]

				R. L. Leshan, G. W. Louis, Y.-H. Jo, C. J. Rhodes, H. Munzberg, and M. G. Myers Jr Direct Innervation of GnRH Neurons by Metabolic- and Sexual Odorant-Sensing Leptin Receptor Neurons in the Hypothalamic Ventral Premammillary Nucleus J. Neurosci., March 11, 2009; 29(10): 3138 - 3147. [Abstract] [Full Text] [PDF]

				G. Yang, C.-Y. Lim, C. Li, X. Xiao, G. K. Radda, C. Li, X. Cao, and W. Han FoxO1 Inhibits Leptin Regulation of Pro-opiomelanocortin Promoter Activity by Blocking STAT3 Interaction with Specificity Protein 1 J. Biol. Chem., February 6, 2009; 284(6): 3719 - 3727. [Abstract] [Full Text] [PDF]

				A. L. Mark, K. Agassandian, D. A. Morgan, X. Liu, M. D. Cassell, and K. Rahmouni Leptin Signaling in the Nucleus Tractus Solitarii Increases Sympathetic Nerve Activity to the Kidney Hypertension, February 1, 2009; 53(2): 375 - 380. [Abstract] [Full Text] [PDF]

				W. Fan, T. Yanase, Y. Nishi, S. Chiba, T. Okabe, M. Nomura, H. Yoshimatsu, S. Kato, R. Takayanagi, and H. Nawata Functional Potentiation of Leptin-Signal Transducer and Activator of Transcription 3 Signaling by the Androgen Receptor Endocrinology, December 1, 2008; 149(12): 6028 - 6036. [Abstract] [Full Text] [PDF]

				R. Khorooshi, A. A. Babcock, and T. Owens NF-{kappa}B-Driven STAT2 and CCL2 Expression in Astrocytes in Response to Brain Injury J. Immunol., November 15, 2008; 181(10): 7284 - 7291. [Abstract] [Full Text] [PDF]

				R. Zhang, H. Dhillon, H. Yin, A. Yoshimura, B. B. Lowell, E. Maratos-Flier, and J. S. Flier Selective Inactivation of Socs3 in SF1 Neurons Improves Glucose Homeostasis without Affecting Body Weight Endocrinology, November 1, 2008; 149(11): 5654 - 5661. [Abstract] [Full Text] [PDF]

				N. C. Bingham, K. K. Anderson, A. L. Reuter, N. R. Stallings, and K. L. Parker Selective Loss of Leptin Receptors in the Ventromedial Hypothalamic Nucleus Results in Increased Adiposity and a Metabolic Syndrome Endocrinology, May 1, 2008; 149(5): 2138 - 2148. [Abstract] [Full Text] [PDF]

				L. Huo, K. M. Gamber, H. J. Grill, and C. Bjorbaek Divergent Leptin Signaling in Proglucagon Neurons of the Nucleus of the Solitary Tract in Mice and Rats Endocrinology, February 1, 2008; 149(2): 492 - 497. [Abstract] [Full Text] [PDF]

				A.-S. Carlo, M. Pyrski, C. Loudes, A. Faivre-Baumann, J. Epelbaum, L. M. Williams, and W. Meyerhof Leptin Sensitivity in the Developing Rat Hypothalamus Endocrinology, December 1, 2007; 148(12): 6073 - 6082. [Abstract] [Full Text] [PDF]

				M. Faouzi, R. Leshan, M. Bjornholm, T. Hennessey, J. Jones, and H. Munzberg Differential Accessibility of Circulating Leptin to Individual Hypothalamic Sites Endocrinology, November 1, 2007; 148(11): 5414 - 5423. [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]

				S. Dziennis, T. Jia, O. K. Ronnekleiv, P. D. Hurn, and N. J. Alkayed Role of Signal Transducer and Activator of Transcription-3 in Estradiol-Mediated Neuroprotection J. Neurosci., July 4, 2007; 27(27): 7268 - 7274. [Abstract] [Full Text] [PDF]

				L. Huo, L. Maeng, C. Bjorbaek, and H. J. Grill Leptin and the Control of Food Intake: Neurons in the Nucleus of the Solitary Tract Are Activated by Both Gastric Distension and Leptin Endocrinology, May 1, 2007; 148(5): 2189 - 2197. [Abstract] [Full Text] [PDF]

				M. Perello, R. C. Stuart, and E. A. Nillni Differential effects of fasting and leptin on proopiomelanocortin peptides in the arcuate nucleus and in the nucleus of the solitary tract Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1348 - E1357. [Abstract] [Full Text] [PDF]

				H. Shimizu, K. Inoue, and M. Mori The leptin-dependent and -independent melanocortin signaling system: regulation of feeding and energy expenditure J. Endocrinol., April 1, 2007; 193(1): 1 - 9. [Abstract] [Full Text] [PDF]

				H. Munzberg, E. E. Jobst, S. H. Bates, J. Jones, E. Villanueva, R. Leshan, M. Bjornholm, J. Elmquist, M. Sleeman, M. A. Cowley, et al. Appropriate Inhibition of Orexigenic Hypothalamic Arcuate Nucleus Neurons Independently of Leptin Receptor/STAT3 Signaling J. Neurosci., January 3, 2007; 27(1): 69 - 74. [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]

				H. Cui, F. Cai, and D. D. Belsham Leptin signaling in neurotensin neurons involves STAT, MAP kinases ERK1/2, and p38 through c-Fos and ATF1 FASEB J, December 1, 2006; 20(14): 2654 - 2656. [Abstract] [Full Text] [PDF]

				C. B. Kaelin, L. Gong, A. W. Xu, F. Yao, K. Hockman, G. J. Morton, M. W. Schwartz, G. S. Barsh, and R. G. MacKenzie Signal Transducer and Activator of Transcription (Stat) Binding Sites But Not Stat3 Are Required for Fasting-Induced Transcription of Agouti-Related Protein Messenger Ribonucleic Acid Mol. Endocrinol., October 1, 2006; 20(10): 2591 - 2602. [Abstract] [Full Text] [PDF]

				K. L.J Ellacott and R. D Cone The role of the central melanocortin system in the regulation of food intake and energy homeostasis: lessons from mouse models Phil Trans R Soc B, July 29, 2006; 361(1471): 1265 - 1274. [Abstract] [Full Text] [PDF]

				R. Janoschek, L. Plum, L. Koch, H. Munzberg, S. Diano, M. Shanabrough, W. Muller, T. L. Horvath, and J. C. Bruning gp130 signaling in proopiomelanocortin neurons mediates the acute anorectic response to centrally applied ciliary neurotrophic factor PNAS, July 11, 2006; 103(28): 10707 - 10712. [Abstract] [Full Text] [PDF]

				K. L. J. Ellacott, I. G. Halatchev, and R. D. Cone Characterization of Leptin-Responsive Neurons in the Caudal Brainstem Endocrinology, July 1, 2006; 147(7): 3190 - 3195. [Abstract] [Full Text] [PDF]

				A. Valerio, V. Ghisi, M. Dossena, C. Tonello, A. Giordano, A. Frontini, M. Ferrario, M. Pizzi, P. Spano, M. O. Carruba, et al. Leptin Increases Axonal Growth Cone Size in Developing Mouse Cortical Neurons by Convergent Signals Inactivating Glycogen Synthase Kinase-3beta J. Biol. Chem., May 5, 2006; 281(18): 12950 - 12958. [Abstract] [Full Text] [PDF]

				L. Huo, H. J. Grill, and C. Bjorbaek Divergent Regulation of Proopiomelanocortin Neurons by Leptin in the Nucleus of the Solitary Tract and in the Arcuate Hypothalamic Nucleus Diabetes, March 1, 2006; 55(3): 567 - 573. [Abstract] [Full Text] [PDF]

				C. D. Morrison, G. J. Morton, K. D. Niswender, R. W. Gelling, and M. W. Schwartz Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling Am J Physiol Endocrinol Metab, December 1, 2005; 289(6): E1051 - E1057. [Abstract] [Full Text] [PDF]

				A. Pocai, K. Morgan, C. Buettner, R. Gutierrez-Juarez, S. Obici, and L. Rossetti Central Leptin Acutely Reverses Diet-Induced Hepatic Insulin Resistance Diabetes, November 1, 2005; 54(11): 3182 - 3189. [Abstract] [Full Text] [PDF]

				M. V. Kokoeva, H. Yin, and J. S. Flier Neurogenesis in the Hypothalamus of Adult Mice: Potential Role in Energy Balance Science, October 28, 2005; 310(5748): 679 - 683. [Abstract] [Full Text] [PDF]

				S. R. Ladyman and D. R. Grattan Suppression of Leptin Receptor Messenger Ribonucleic Acid and Leptin Responsiveness in the Ventromedial Nucleus of the Hypothalamus during Pregnancy in the Rat Endocrinology, September 1, 2005; 146(9): 3868 - 3874. [Abstract] [Full Text] [PDF]

				F. S. J. de Souza, A. M. Santangelo, V. Bumaschny, M. E. Avale, J. L. Smart, M. J. Low, and M. Rubinstein Identification of Neuronal Enhancers of the Proopiomelanocortin Gene by Transgenic Mouse Analysis and Phylogenetic Footprinting Mol. Cell. Biol., April 15, 2005; 25(8): 3076 - 3086. [Abstract] [Full Text] [PDF]

				H. Munzberg, J. S. Flier, and C. Bjorbaek Region-Specific Leptin Resistance within the Hypothalamus of Diet-Induced Obese Mice Endocrinology, November 1, 2004; 145(11): 4880 - 4889. [Abstract] [Full Text] [PDF]

				L. Guo, H. Munzberg, R. C. Stuart, E. A. Nillni, and C. Bjorbaek N-acetylation of hypothalamic {alpha}-melanocyte-stimulating hormone and regulation by leptin PNAS, August 10, 2004; 101(32): 11797 - 11802. [Abstract] [Full Text] [PDF]

				A. Sahu Minireview: A Hypothalamic Role in Energy Balance with Special Emphasis on Leptin Endocrinology, June 1, 2004; 145(6): 2613 - 2620. [Abstract] [Full Text] [PDF]

				L. Huo, H. Munzberg, E. A. Nillni, and C. Bjorbaek Role of Signal Transducer and Activator of Transcription 3 in Regulation of Hypothalamic trh Gene Expression by Leptin Endocrinology, May 1, 2004; 145(5): 2516 - 2523. [Abstract] [Full Text] [PDF]

				F. Guo, K. Bakal, Y. Minokoshi, and A. N. Hollenberg Leptin Signaling Targets the Thyrotropin-Releasing Hormone Gene Promoter in Vivo Endocrinology, May 1, 2004; 145(5): 2221 - 2227. [Abstract] [Full Text] [PDF]

				E. Jing, E. A. Nillni, V. C. Sanchez, R. C. Stuart, and D. J. Good Deletion of the Nhlh2 Transcription Factor Decreases the Levels of the Anorexigenic Peptides {alpha} Melanocyte-Stimulating Hormone and Thyrotropin-Releasing Hormone and Implicates Prohormone Convertases I and II in Obesity Endocrinology, April 1, 2004; 145(4): 1503 - 1513. [Abstract] [Full Text] [PDF]

				C. Bjorbaek and B. B. Kahn Leptin Signaling in the Central Nervous System and the Periphery Recent Prog. Horm. Res., January 1, 2004; 59(1): 305 - 331. [Abstract] [Full Text]

				K. L.J. Ellacott and R. D. Cone The Central Melanocortin System and the Integration of Short- and Long-term Regulators of Energy Homeostasis Recent Prog. Horm. Res., January 1, 2004; 59(1): 395 - 408. [Abstract] [Full Text]