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The role of growth hormone in the brain: relevance for neural functions and in disease

Abstract

GH is the most abundant factor secreted by the pituitary gland and plays an important role controlling somatic and tissue growth, as well as cell proliferation and differentiation. Despite the presence of the GH Receptor (GHR) in the brain, little is known about the effects of this hormone on the nervous system. Thus, we propose in this project that GH has a previously unrecognized role in the nervous system. Our hypothesis is that the brain mediates important aspects of the biological effects of GH, particularly regarding the metabolism. Therefore, the aim of the present project is to investigate the importance of GH signaling in the nervous system by manipulating GHR expression in specific populations of neurons. To do so, we will use mice from the Cre/loxP system that allow the inactivation of GHR or its main intracellular signaling pathway, STAT5, in neuronal populations of interest. We will produce mice with selective inactivation of GHR and/or STAT5 throughout the nervous system, in leptin receptor-expressing cells, in neurons of the ventromedial nucleus of the hypothalamus (SF1 positive cells) and in neurons expressing AgRP, orexin or tyrosine hydroxylase. These different mouse models will be studied in 14 subprojects aimed at investigating the importance of central GH signaling in multiple neurological functions, including metabolic control, cognition, wake-sleep cycle, memory/learning, behavior, emotions/motivation, as well as in neurovegetative and neuroendocrine functions. The knowledge that will be generated by the experiments proposed may change our notion about the function and mechanisms of action of one of the most important hormones. (AU)

Articles published in Pesquisa FAPESP Magazine about the research grant:
Enemigo de las dietas 
An enemy unknown 
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VEICULO: TITULO (DATA)
VEICULO: TITULO (DATA)

Scientific publications (36)
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
MOURA-ASSIS, ALEXANDRE; NOGUEIRA, PEDRO A. S.; DE-LIMA-JUNIOR, JOSE C.; SIMABUCO, FERNANDO M.; GASPAR, JOANA M.; DONATO JR, JOSE; VELLOSO, LICIO A. TLR4-interactor with leucine-rich repeats (TRIL) is involved in diet-induced hypothalamic inflammation. SCIENTIFIC REPORTS, v. 11, n. 1 SEP 9 2021. Web of Science Citations: 0.
WASINSKI, FREDERICK; CHAVES, FERNANDA M.; PEDROSO, JOAO A. B.; MANSANO, NAIRA S.; CAMPOREZ, JOAO PAULO; GUSMAO, DANIELA O.; LIST, EDWARD O.; KOPCHICK, JOHN J.; FRAZAO, RENATA; SZAWKA, RAPHAEL E.; DONATO, JR., JOSE. Growth hormone receptor in dopaminergic neurones regulates stress-induced prolactin release in male mice. Journal of Neuroendocrinology, v. 33, n. 3 MAR 2021. Web of Science Citations: 0.
WASINSKI, FREDERICK; KLEIN, MARIANNE O.; BITTENCOURT, JACKSON C.; METZGER, MARTIN; DONATO JR, JOSE. Distribution of growth hormone-responsive cells in the brain of rats and mice. Brain Research, v. 1751, JAN 15 2021. Web of Science Citations: 1.
FLORES, RAFAEL APPEL; STEINBACH, RENATA; PEDROSO, JOAO A. B.; METZGER, MARTIN; DONATO, JR., JOSE; PASCHOALINI, MARTA APARECIDA. Injections of the alpha-2 adrenoceptor agonist clonidine into the dorsal raphe nucleus increases food intake in satiated rats. Neuropharmacology, v. 182, JAN 2021. Web of Science Citations: 0.
PEDROSO, JOAO A. B.; DOS SANTOS, LUCAS B. P.; FURIGO, ISADORA C.; SPAGNOL, ALEXANDRE R.; WASINSKI, FREDERICK; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO JR, JOSE. Deletion of growth hormone receptor in hypothalamic neurons affects the adaptation capacity to aerobic exercise. Peptides, v. 135, JAN 2021. Web of Science Citations: 1.
CHAVES, FERNANDA M.; MANSANO, NAIRA S.; FRAZAO, RENATA; DONATO JR, JOSE. Tumor Necrosis Factor alpha and Interleukin-1 beta Acutely Inhibit AgRP Neurons in the Arcuate Nucleus of the Hypothalamus. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 21, n. 23 DEC 2020. Web of Science Citations: 0.
QUARESMA, PAULA G. F.; TEIXEIRA, PRYSCILA D. S.; WASINSKI, FREDERICK; CAMPOS, ANA M. P.; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO, JR., JOSE. Cholinergic neurons in the hypothalamus and dorsal motor nucleus of the vagus are directly responsive to growth hormone. Life Sciences, v. 259, OCT 15 2020. Web of Science Citations: 0.
PEDROSO, JOAO A. B.; WASINSKI, FREDERICK; DONATO JR, JOSE. Prolonged fasting induces long-lasting metabolic consequences in mice. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 84, OCT 2020. Web of Science Citations: 0.
QUARESMA, PAULA G. F.; DOS SANTOS, WILLIAN O.; WASINSKI, FREDERICK; METZGER, MARTIN; DONATO JR, JOSE. Neurochemical phenotype of growth hormone-responsive cells in the mouse paraventricular nucleus of the hypothalamus. JOURNAL OF COMPARATIVE NEUROLOGY, v. 529, n. 6 SEP 2020. Web of Science Citations: 2.
ZAMPIERI, THAIS TESSARI; BOHLEN, TABATA MARIZ; SILVEIRA, MARINA AUGUSTO; LANA, LARISSA CAMPISTA; DE PAULA, DANIELLA G.; DONATO, JOSE; FRAZAO, RENATA. Postnatal Overnutrition Induces Changes in Synaptic Transmission to Leptin Receptor-Expressing Neurons in the Arcuate Nucleus of Female Mice. NUTRIENTS, v. 12, n. 8 AUG 2020. Web of Science Citations: 0.
CAMPOS, ANA M. P.; TEIXEIRA, PRYSCILA D. S.; WASINSKI, FREDERICK; KLEIN, MARIANNE O.; BITTENCOURT, JACKSON C.; METZGER, MARTIN; DONATO, JR., JOSE. Differences between rats and mice in the leptin action on the paraventricular nucleus of the hypothalamus: Implications for the regulation of the hypothalamic-pituitary-thyroid axis. Journal of Neuroendocrinology, AUG 2020. Web of Science Citations: 1.
CAMPOLIM, CLARA MACHADO; WEISSMANN, LAIS; DE OLIVEIRA FERREIRA, CLILTON KRAUESS; ZORDAO, OLIVIA PIZETTA; SEGANTINE DORNELLAS, ANA PAULA; DE CASTRO, GISELE; ZANOTTO, TAMIRES MARQUES; BOICO, VITOR FERREIRA; FERNANDES QUARESMA, PAULA GABRIELE; ATAIDE LIMA, RAQUEL PATRICIA; DONATO, JOSE; VERAS, MARIANA MATERA; NASCIMENTO SALDIVA, PAULO HILARIO; KIM, YOUNG-BUM; PRADA, PATRICIA OLIVEIRA. Short-term exposure to air pollution (PM2.5) induces hypothalamic inflammation, and long-term leads to leptin resistance and obesity via Tlr4/Ikbke in mice. SCIENTIFIC REPORTS, v. 10, n. 1 JUN 23 2020. Web of Science Citations: 0.
WASINSKI, FREDERICK; PEDROSO, JOAO A. B.; DOS SANTOS, WILLIAN O.; FURIGO, ISADORA C.; GARCIA-GALIANO, DAVID; ELIAS, CAROL F.; LIST, EDWARD O.; KOPCHICK, JOHN J.; SZAWKA, RAPHAEL E.; DONATO JR, JOSE. Tyrosine Hydroxylase Neurons Regulate Growth Hormone Secretion via Short-Loop Negative Feedback. JOURNAL OF NEUROSCIENCE, v. 40, n. 22, p. 4309-4322, MAY 27 2020. Web of Science Citations: 0.
WASINSKI, FREDERICK; FURIGO, ISADORA C.; TEIXEIRA, PRYSCILA D. S.; RAMOS-LOBO, ANGELA M.; PERONI, CIBELE N.; BARTOLINI, PAOLO; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO JR, JOSE. Growth Hormone Receptor Deletion Reduces the Density of Axonal Projections from Hypothalamic Arcuate Nucleus Neurons. Neuroscience, v. 434, p. 136-147, MAY 10 2020. Web of Science Citations: 0.
FURIGO, ISADORA C.; TEIXEIRA, PRYSCILA D. S.; QUARESMA, PAULA G. F.; MANSANO, NAIRA S.; FRAZAO, RENATA; DONATO JR, JOSE. STAT5 ablation in AgRP neurons increases female adiposity and blunts food restriction adaptations. JOURNAL OF MOLECULAR ENDOCRINOLOGY, v. 64, n. 1, p. 13-27, JAN 2020. Web of Science Citations: 0.
BUENO, DEBORA; LIMA, LEANDRO B.; SOUZA, RUDIERI; GONCALVES, LUCIANO; LEITE, FERNANDA; SOUZA, STEFANI; FURIGO, ISADORA C.; DONATO, JR., JOSE; METZGER, MARTIN. Connections of the laterodorsal tegmental nucleus with the habenular-interpeduncular-raphe system. JOURNAL OF COMPARATIVE NEUROLOGY, v. 527, n. 18, p. 3046-3072, DEC 15 2019. Web of Science Citations: 2.
QUARESMA, PAULA G. F.; TEIXEIRA, PRYSCILA D. S.; FURIGO, ISADORA C.; WASINSKI, FREDERICK; COUTO, GISELE C.; FRAZAO, RENATA; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO JR, JOSE. Growth hormone/STAT5 signaling in proopiomelanocortin neurons regulates glucoprivic hyperphagia. Molecular and Cellular Endocrinology, v. 498, DEC 1 2019. Web of Science Citations: 2.
BOHLEN, TABATA M.; ZAMPIERI, THAIS T.; FURIGO, ISADORA C.; TEIXEIRA, PRYSCILA D. S.; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO, JR., JOSE; FRAZAO, RENATA. Central growth hormone signaling is not required for the timing of puberty. Journal of Endocrinology, v. 243, n. 3, p. 161-173, DEC 2019. Web of Science Citations: 2.
METZGER, MARTIN; SOUZA, RUDIERI; LIMA, LEANDRO B.; BUENO, DEBORA; GONCALVES, LUCIANO; SEGO, CHEMUTAI; DONATO, JR., JOSE; SHAMMAH-LAGNADO, SARA J. Habenular connections with the dopaminergic and serotonergic system and their role in stress-related psychiatric disorders. European Journal of Neuroscience, v. 53, n. 1, SI DEC 2019. Web of Science Citations: 5.
PEDROSO, JOAO A. B.; CAMPOREZ, JOAO PAULO; BELPIEDE, LUCIANA T.; PINTO, RAFAELA S.; CIPOLLA-NETO, JOSE; DONATO, JOSE. Evaluation of Hepatic Steatosis in Rodents by Time-Domain Nuclear Magnetic Resonance. DIAGNOSTICS, v. 9, n. 4 DEC 2019. Web of Science Citations: 0.
TEIXEIRA, PRYSCILA D. S.; WASINSKI, FREDERICK; LIMA, LEANDRO B.; FRAZAO, RENATA; BITTENCOURT, JACKSON C.; DONATO JR, JOSE. Regulation and neurochemical identity of melanin-concentrating hormone neurones in the preoptic area of lactating mice. Journal of Neuroendocrinology, v. 32, n. 2 DEC 2019. Web of Science Citations: 0.
TEIXEIRA, PRYSCILA D. S.; RAMOS-LOBO, ANGELA M.; FURIGO, ISADORA C.; DONATO, JR., JOSE. Brain STAT5 Modulates Long-Term Metabolic and Epigenetic Changes Induced by Pregnancy and Lactation in Female Mice. Endocrinology, v. 160, n. 12, p. 2903-2917, DEC 2019. Web of Science Citations: 1.
FREDERICK WASINSKI; RENATA FRAZÃO; JOSE DONATO JR. Effects of growth hormone in the central nervous system. ARCHIVES OF ENDOCRINOLOGY METABOLISM, v. 63, n. 6, p. 549-556, Nov. 2019. Web of Science Citations: 1.
FURIGO, ISADORA C.; DE SOUZA, GABRIEL O.; TEIXEIRA, PRYSCILA D. S.; GUADAGNINI, DIOZE; FRAZAO, RENATA; LIST, EDWARD O.; KOPCHICK, JOHN J.; PRADA, PATRICIA O.; DONATO, JR., JOSE. Growth hormone enhances the recovery of hypoglycemia via ventromedial hypothalamic neurons. FASEB JOURNAL, v. 33, n. 11, p. 11909-11924, NOV 2019. Web of Science Citations: 2.
TEIXEIRA, PRYSCILA D. S.; COUTO, GISELE C.; FURIGO, ISADORA C.; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO, JR., JOSE. Central growth hormone action regulates metabolism during pregnancy. AMERICAN JOURNAL OF PHYSIOLOGY-ENDOCRINOLOGY AND METABOLISM, v. 317, n. 5, p. E925-E940, NOV 2019. Web of Science Citations: 1.
BUONFIGLIO, DANIELLA; TCHIO, CYNTHIA; FURIGO, ISADORA; DONATO, JR., JOSE; BABA, KENKICHI; CIPOLLA-NETO, JOSE; TOSINI, GIANLUCA. Removing melatonin receptor type 1 signaling leads to selective leptin resistance in the arcuate nucleus. Journal of Pineal Research, v. 67, n. 2 SEP 2019. Web of Science Citations: 2.
LIMA, LEANDRO B.; PEDROSO, JOAO A. B.; METZGER, MARTIN; GAUTRON, LAURENT; DONATO, JR., JOSE. Relationship of alpha-MSH and AgRP axons to the perikarya of melanocortin-4 receptor neurons. Brain Research, v. 1717, p. 136-146, AUG 15 2019. Web of Science Citations: 0.
SILVEIRA, MARINA A.; ZAMPIERI, THAIS T.; FURIGO, ISADORA C.; ABDULKADER, FERNANDO; DONATO, JR., JOSE; FRAZAO, RENATA. Acute effects of somatomammotropin hormones on neuronal components of the hypothalamic-pituitary-gonadal axis. Brain Research, v. 1714, p. 210-217, JUL 1 2019. Web of Science Citations: 3.
ANDREOLI, MARFA F.; DONATO JR, JOSE; CAKIR, ISIN; PERELLO, MARIO. Leptin resensitisation: a reversion of leptin-resistant states. Journal of Endocrinology, v. 241, n. 3, p. R81-R96, JUN 2019. Web of Science Citations: 4.
PEDROSO, JOAO A. B.; RAMOS-LOBO, ANGELA M.; DONATO, JR., JOSE. SOCS3 as a future target to treat metabolic disorders. HORMONES-INTERNATIONAL JOURNAL OF ENDOCRINOLOGY AND METABOLISM, v. 18, n. 2, p. 127-136, JUN 2019. Web of Science Citations: 3.
FURIGO, ISADORA C.; TEIXEIRA, PRYSCILA D. S.; DE SOUZA, GABRIEL O.; COUTO, GISELE C. L.; GARCIA ROMERO, GUADALUPE; PERELLO, MARIO; FRAZAO, RENATA; ELIAS, LUCILA L.; METZGER, MARTIN; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO, JR., J. Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons. NATURE COMMUNICATIONS, v. 10, FEB 8 2019. Web of Science Citations: 10.
DE ARAUJO, THIAGO MATOS; RAZOLLI, DANIELA S.; CORREA-DA-SILVA, FELIPE; DE LIMA-JUNIOR, JOSE C.; GASPAR, RODRIGO S.; SIDARTA-OLIVEIRA, DAVI; VICTORIO, SHEILA C.; DONATO, JR., JOSE; KIM, YOUNG-BUM; VELLOSO, LICIO A. The partial inhibition of hypothalamic IRX3 exacerbates obesity. EBIOMEDICINE, v. 39, p. 448-460, JAN 2019. Web of Science Citations: 5.
MENDES, NATALIA F.; KIM, YOUNG-BUM; VELLOSO, LICIO A.; ARAUJO, ELIANA P. Hypothalamic Microglial Activation in Obesity: A Mini-Review. FRONTIERS IN NEUROSCIENCE, v. 12, NOV 15 2018. Web of Science Citations: 10.
LIMA, LEANDRO BUENO; HAUBENTHAL, FERNANDA TAIS; SILVEIRA, MARINA AUGUSTO; BOHLEN, TABATA MARIZ; METZGER, MARTIN; DONATO JR, JOSE; FRAZAO, RENATO. Conspecific odor exposure predominantly activates non-kisspeptin cells in the medial nucleus of the amygdala. Neuroscience Letters, v. 681, p. 12-16, AUG 10 2018. Web of Science Citations: 3.
MENDES, NATALIA F.; GASPAR, JOANA M.; LIMA-JUNIOR, JOSE C.; DONATO, JR., JOSE; VELLOSO, LICIO A.; ARAUJO, ELIANA P. TGF-beta 1 down-regulation in the mediobasal hypothalamus attenuates hypothalamic inflammation and protects against diet-induced obesity. METABOLISM-CLINICAL AND EXPERIMENTAL, v. 85, p. 171-182, AUG 2018. Web of Science Citations: 7.
FURIGO, ISADORA C.; MELO, HELEN M.; LYRA E SILVA, NATALIA M.; RAMOS-LOBO, ANGELA M.; TEIXEIRA, PRYSCILA D. S.; BUONFIGLIO, DANIELLA C.; WASINSKI, FREDERICK; LIMA, ELIANA R.; HIGUTI, ELIZA; PERONI, CIBELE N.; BARTOLINI, PAOLO; SOARES, CARLOS R. J.; METZGER, MARTIN; DE FELICE, FERNANDA G.; DONATO, JR., JOSE. Brain STAT5 signaling modulates learning and memory formation. Brain Structure & Function, v. 223, n. 5, p. 2229-2241, JUN 2018. Web of Science Citations: 9.

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