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Abstract:

Signal transducer and activator of transcription (Stat)-3 signals mediate many of the metabolic effects of the fat cell-derived hormone, leptin. In mice, brain-specific depletion of either the long form of the leptin receptor (Lepr) or Stat3 results in comparable obese phenotypes as does replacement of Lepr with an altered leptin receptor locus that codes for a Lepr unable to interact with Stat3. Among the multiple brain regions containing leptin-sensitive Stat3 sites, cells expressing feeding-related neuropeptides in the arcuate nucleus of the hypothalamus have received much of the focus. To determine the contribution to energy homeostasis of Stat3 expressed in agouti-related protein (Agrp)/neuropeptide Y (Npy) arcuate neurons, Stat3 was deleted specifically from these cells, and several metabolic indices were measured. It was found that deletion of Stat3 from Agrp/Npy neurons resulted in modest weight gain that was accounted for by increased adiposity. Agrp/Stat3-deficient mice also showed hyperleptinemia, and high-fat diet-induced hyperinsulinemia. Stat3 deletion in Agrp/Npy neurons also resulted in altered hypothalamic gene expression indicated by increased Npy mRNA and decreased induction of suppressor of cytokine signaling-3 in response to leptin. Agrp mRNA levels in the fed or fasted state were unaffected. Behaviorally, mice without Stat3 in Agrp/Npy neurons were mildly hyperphagic and hyporesponsive to leptin. We conclude that Stat3 in Agrp/Npy neurons is required for normal energy homeostasis, but Stat3 signaling in other brain areas also contributes to the regulation of energy homeostasis. Copyright © 2008 by The Endocrine Society.

Registro:

Documento: Artículo
Título:Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis
Autor:Gong, L.; Yao, F.; Hockman, K.; Heng, H.H.; Morton, G.J.; Takeda, K.; Akira, S.; Low, M.J.; Rubinstein, M.; MacKenzie, R.G.
Filiación:Department of Psychiatry and Behavioral Neurosciences, Center for Integrative Endocrine and Metabolic Research, Wayne State University School of Medicine, Detroit, MI 48201, United States
Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI 48201, United States
Division of Metabolism, Endocrinology and Nutrition, University of Washington, Seattle, WA 98104, United States
Department of Molecular Genetics, Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8581, Japan
Department of Host Defense, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Center for the Study of Weight Regulation, Department of Behavioral Neuroscience, Oregon Health and Science University, Portland, OR 97239, United States
Inst. de Invest. en Ingenieria Genet. Y Biologia Molec. (Consejo Nac. de Invest. Cientificas Y Tec.), Department of Physiology, Molecular, and Cellular Biology, Universidad de Buenos Aires, Buenos Aires 1428, Argentina
Department of Psychiatry and Behavioral Neurosciences, Wayne State University School of Medicine, 103 Lande Building, 550 East Canfield, Detroit, MI 48201, United States
Palabras clave:agouti related protein; leptin receptor; neuropeptide Y; STAT3 protein; animal tissue; arcuate nucleus; article; body weight; brain region; controlled study; gene locus; homeostasis; hyperleptinemia; hyperphagia; hypothalamus; lipid diet; mouse; nonhuman; nucleotide sequence; obesity; phenotype; priority journal; protein expression; signal transduction; Adiposity; Agouti-Related Protein; Animals; Body Weight; Dietary Fats; Energy Metabolism; Homeostasis; Hypothalamus; Immunohistochemistry; Leptin; Mice; Neurons; Neuropeptide Y; Reverse Transcriptase Polymerase Chain Reaction; STAT3 Transcription Factor; Weight Gain
Año:2008
Volumen:149
Número:7
Página de inicio:3346
Página de fin:3354
DOI: http://dx.doi.org/10.1210/en.2007-0945
Título revista:Endocrinology
Título revista abreviado:Endocrinology
ISSN:00137227
CODEN:ENDOA
CAS:neuropeptide Y, 82785-45-3, 83589-17-7; Agouti-Related Protein; Dietary Fats; Leptin; Neuropeptide Y; STAT3 Transcription Factor
Registro:https://bibliotecadigital.exactas.uba.ar/collection/paper/document/paper_00137227_v149_n7_p3346_Gong

Referencias:

  • Friedman, J.M., Halaas, J.L., Leptin and the regulation of body weight in mammals (1998) Nature, 395, pp. 763-770
  • Cohen, P., Zhao, C., Cai, X., Montez, J.M., Rohani, S.C., Feinstein, P., Mombaerts, P., Friedman, J.M., Selective deletion of leptin receptor in neurons leads to obesity (2001) J Clin Invest, 108, pp. 1113-1121
  • Dhillon, H., Zigman, J.M., Ye, C., Lee, C.E., McGovern, R.A., Tang, V., Kenny, C.D., Lowell, B.B., Leptin directly activates SF1 neurons in the VMH, and this action by leptin is required for normal body-weight homeostasis (2006) Neuron, 49, pp. 191-203
  • Grill HJ 2006 Distributed neural control of energy balance: contributions from hindbrain and hypothalamus. Obesity (Silver Spring) 14(Suppl 5):216S-221S; Leinninger, G.M., Myers Jr, M.G., LRb signals act within a distributed network of leptin-responsive neurones to mediate leptin action (2008) Acta Physiol (Oxf), 192, pp. 49-59
  • Morton, G.J., Cummings, D.E., Baskin, D.G., Barsh, G.S., Schwartz, M.W., Central nervous system control of food intake and body weight (2006) Nature, 443, pp. 289-295
  • Tartaglia, L.A., Dembski, M., Weng, X., Deng, N., Culpepper, J., Devos, R., Richards, G.J., Tepper, R.I., Identification and expression cloning of a leptin receptor, OB-R (1995) Cell, 83, pp. 1263-1271
  • Gao, Q., Wolfgang, M.J., Neschen, S., Morino, K., Horvath, T.L., Shulman, G.I., Fu, X.Y., Disruption of neural signal transducer and activator of transcription 3 causes obesity, diabetes, infertility, and thermal dysregulation (2004) Proc Natl Acad Sci, 101, pp. 4661-4666. , USA
  • Bates, S.H., Stearns, W.H., Dundon, T.A., Schubert, M., Tso, A.W., Wang, Y., Banks, A.S., Myers Jr, M.G., STAT3 signalling is required for leptin regulation of energy balance but not reproduction (2003) Nature, 421, pp. 856-859
  • Cowley, M.A., Smart, J.L., Rubinstein, M., Cerdan, M.G., Diano, S., Horvath, T.L., Cone, R.D., Low, M.J., Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus (2001) Nature, 411, pp. 480-484
  • Schwartz, M.W., Seeley, R.J., Woods, S.C., Weigle, D.S., Campfield, L.A., Burn, P., Baskin, D.G., Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus (1997) Diabetes, 46, pp. 2119-2123
  • Takahashi, K.A., Cone, R.D., Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/agouti-related protein neurons (2005) Endocrinology, 146, pp. 1043-1047
  • Stanley, B.G., Kyrkouli, S.E., Lampert, S., Leibowitz, S.F., Neuropeptide Y chronically injected into the hypothalamus: A powerful neurochemical inducer of hyperphagia and obesity (1986) Peptides, 7, pp. 1189-1192
  • Taylor, K., Lester, E., Hudson, B., Ritter, S., Hypothalamic and hindbrain NPY, AGRP and NE increase consummatory feeding responses (2007) Physiol Behav, 90, pp. 744-750
  • Balthasar, N., Coppari, R., McMinn, J., Liu, S.M., Lee, C.E., Tang, V., Kenny, C.D., Lowell, B.B., Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis (2004) Neuron, 42, pp. 983-991
  • Xu, A.W., Ste, Marie, L., Kaelin, C.B., Barsh, G.S., Inactivation of signal transducer and activator of transcription 3 in proopiomelanocortin (Pomc) neurons causes decreased pomc expression, mild obesity, and defects in compensatory refeeding (2007) Endocrinology, 148, pp. 72-80
  • Kaelin, C.B., Gong, L., Xu, A.W., Yao, F., Hockman, K., Morton, G.J., Schwartz, M.W., MacKenzie, R.G., 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 (2006) Mol Endocrinol, 20, pp. 2591-2602
  • Fink, L., Seeger, W., Ermert, L., Hanze, J., Stahl, U., Grimminger, F., Kummer, W., Bohle, R.M., Real-time quantitative RT-PCR after laser-assisted cell picking (1998) Nat Med, 4, pp. 1329-1333
  • Livak, K.J., Schmittgen, T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2[-ΔΔC(T)] method (2001) Methods, 25, pp. 402-408
  • Cui, Y., Huang, L., Elefteriou, F., Yang, G., Shelton, J.M., Giles, J.E., Oz, O.K., Li, C., Essential role of STAT3 in body weight and glucose homeostasis (2004) Mol Cell Biol, 24, pp. 258-269
  • Maffei, M., Halaas, J., Ravussin, E., Pratley, R.E., Lee, G.H., Zhang, Y., Fei, H., Friedman, J.M., Leptin levels in human and rodent: Measurement of plasma leptin and ob RNA in obese and weight-reduced subjects (1995) Nat Med, 1, pp. 1155-1161
  • Piper, M.L., Unger, E.K., Myers Jr, M.G., Xu, A.W., Specific physiological roles for Stat3 in leptin receptor-expressing neurons (2007) Mol Endocrinol, 22, pp. 751-759
  • Bates, S.H., Kulkarni, R.N., Seifert, M., Myers Jr, M.G., Roles for leptin receptor/STAT3-dependent and -independent signals in the regulation of glucose homeostasis (2005) Cell Metab, 1, pp. 169-178
  • Enriori PJ, Evans AE, Sinnayah P, Cowley MA 2006 Leptin resistance and obesity. Obesity (Silver Spring) 14(Suppl 5):254S-258S; Munzberg, H., Myers Jr, M.G., Molecular and anatomical determinants of central leptin resistance (2005) Nat Neurosci, 8, pp. 566-570
  • Munzberg, H., Flier, J.S., Bjorbaek, C., Region-specific leptin resistance within the hypothalamus of diet-induced obese mice (2004) Endocrinology, 145, pp. 4880-4889
  • Balthasar N 2006 Genetic dissection of neuronal pathways controlling energy homeostasis. Obesity (Silver Spring) 14(Suppl 5):222S-227S; Hommel, J.D., Trinko, R., Sears, R.M., Georgescu, D., Liu, Z.W., Gao, X.B., Thurmon, J.J., DiLeone, R.J., Leptin receptor signaling in midbrain dopamine neurons regulates feeding (2006) Neuron, 51, pp. 801-810
  • van den Top, M., Lee, K., Whyment, A.D., Blanks, A.M., Spanswick, D., Orexigen-sensitive NPY/AgRP pacemaker neurons in the hypothalamic arcuate nucleus (2004) Nat Neurosci, 7, pp. 493-494
  • Munzberg, H., Jobst, E.E., Bates, S.H., Jones, J., Villanueva, E., Leshan, R., Bjornholm, M., Myers Jr, M.G., Appropriate inhibition of orexigenic hypothalamic arcuate nucleus neurons independently of leptin receptor/STAT3 signaling (2007) J Neurosci, 27, pp. 69-74
  • Claret, M., Smith, M.A., Batterham, R.L., Selman, C., Choudhury, A.I., Fryer, L.G., Clements, M., Withers, D.J., AMPK is essential for energy homeostasis regulation and glucose sensing by POMC and AgRP neurons (2007) J Clin Invest, 117, pp. 2325-2336
  • Coppola, A., Liu, Z.W., Andrews, Z.B., Paradis, E., Roy, M.C., Friedman, J.M., Ricquier, D., Diano, S., A central thermogenic-like mechanism in feeding regulation: An interplay between arcuate nucleus T3 and UCP2 (2007) Cell Metab, 5, pp. 21-33
  • Konner, A.C., Janoschek, R., Plum, L., Jordan, S.D., Rother, E., Ma, X., Xu, C., Bruning, J.C., Insulin action in AgRP-expressing neurons is required for suppression of hepatic glucose production (2007) Cell Metab, 5, pp. 438-449
  • Nakazato, M., Murakami, N., Date, Y., Kojima, M., Matsuo, H., Kangawa, K., Matsukura, S., role for ghrelin in the central regulation of feeding (2001) Nature, 409, pp. 194-198
  • Xu, A.W., Kaelin, C.B., Takeda, K., Akira, S., Schwartz, M.W., Barsh, G.S., PI3K integrates the action of insulin and leptin on hypothalamic neurons (2005) J Clin Invest, 115, pp. 951-958
  • Kitamura, T., Feng, Y., Kitamura, Y.I., Chua Jr, S.C., Xu, A.W., Barsh, G.S., Rossetti, L., Accili, D., Forkhead protein FoxO1 mediates Agrp-dependent effects of leptin on food intake (2006) Nat Med, 12, pp. 534-540
  • Mutze, J., Roth, J., Gerstberger, R., Hubschle, T., Nuclear translocation of the transcription factor STAT5 in the rat brain after systemic leptin administration (2007) Neurosci Lett, 417, pp. 286-291
  • Morrison, C.D., Morton, G.J., Niswender, K.D., Gelling, R.W., Schwartz, M.W., Leptin inhibits hypothalamic Npy and Agrp gene expression via a mechanism that requires phosphatidylinositol 3-OH-kinase signaling (2005) Am J Physiol Endocrinol Metab, 289, pp. E1051-E1057
  • Sakkou, M., Wiedmer, P., Anlag, K., Hamm, A., Seuntjens, E., Ettwiller, L., Tschop, M.H., Treier, M., A role for brain-specific homeobox factor bsx in the control of hyperphagia and locomotory behavior (2007) Cell Metab, 5, pp. 450-463

Citas:

---------- APA ----------
Gong, L., Yao, F., Hockman, K., Heng, H.H., Morton, G.J., Takeda, K., Akira, S.,..., MacKenzie, R.G. (2008) . Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis. Endocrinology, 149(7), 3346-3354.
http://dx.doi.org/10.1210/en.2007-0945
---------- CHICAGO ----------
Gong, L., Yao, F., Hockman, K., Heng, H.H., Morton, G.J., Takeda, K., et al. "Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis" . Endocrinology 149, no. 7 (2008) : 3346-3354.
http://dx.doi.org/10.1210/en.2007-0945
---------- MLA ----------
Gong, L., Yao, F., Hockman, K., Heng, H.H., Morton, G.J., Takeda, K., et al. "Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis" . Endocrinology, vol. 149, no. 7, 2008, pp. 3346-3354.
http://dx.doi.org/10.1210/en.2007-0945
---------- VANCOUVER ----------
Gong, L., Yao, F., Hockman, K., Heng, H.H., Morton, G.J., Takeda, K., et al. Signal transducer and activator of transcription-3 is required in hypothalamic agouti-related protein/neuropeptide Y neurons for normal energy homeostasis. Endocrinology. 2008;149(7):3346-3354.
http://dx.doi.org/10.1210/en.2007-0945