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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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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)
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, . (17/16473-6, 14/08755-3, 17/02983-2, 12/12202-4, 15/14588-5)
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, . (16/09679-4, 15/20198-5, 13/07908-8, 17/02983-2)
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, . (17/22511-8, 13/07607-8, 17/02983-2, 16/17810-3)
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.; et al. Brain STAT5 signaling modulates learning and memory formation. Brain Structure & Function, v. 223, n. 5, p. 2229-2241, . (16/09679-4, 16/20897-3, 14/11752-6, 12/02388-3, 12/24345-4, 17/02983-2, 15/10992-6)
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.; et al. Growth hormone regulates neuroendocrine responses to weight loss via AgRP neurons. NATURE COMMUNICATIONS, v. 10, . (16/09679-4, 17/04006-4, 17/21840-8, 17/16473-6, 17/05007-4, 17/02983-2)
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.; et al. Growth hormone receptor in dopaminergic neurones regulates stress-induced prolactin release in male mice. Journal of Neuroendocrinology, v. 33, n. 3, . (18/04956-5, 17/02983-2, 20/01318-8, 17/21840-8, 16/20897-3, 17/21854-9, 17/22189-9)
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, . (14/50457-0, 17/02983-2, 15/26190-6)
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, . (16/20897-3, 14/11752-6, 17/02983-2, 16/09679-4)
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, . (17/16473-6, 17/02983-2, 12/15517-6)
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, . (16/09679-4, 17/04006-4, 17/21840-8, 17/25281-3, 16/20897-3, 17/02983-2)
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, . (13/07607-8, 16/17810-3, 17/02983-2, 15/10078-2)
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, . (16/09679-4, 17/18498-6, 17/02983-2, 18/20087-7)
PEDROSO, JOAO A. B.; WASINSKI, FREDERICK; DONATO JR, JOSE. Prolonged fasting induces long-lasting metabolic consequences in mice. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 84, . (17/02983-2, 16/20897-3)
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, . (17/02983-2, 17/25281-3, 16/20897-3)
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, . (16/09679-4, 17/16473-6, 17/02983-2)
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, . (16/20897-3, 17/02983-2, 16/09679-4)
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, . (16/09679-4, 15/20198-5, 15/14588-5, 17/02983-2)
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, . (16/20897-3, 17/25281-3, 17/16473-6, 17/02983-2)
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, . (16/03082-6, 17/02983-2, 13/07908-8, 15/14588-5, 15/20198-5)
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, . (20/01318-8, 17/21840-8, 17/22189-9, 17/21854-9, 17/02983-2)
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, . (17/16473-6, 16/20897-3, 17/02983-2, 16/02224-1, 17/17998-5)
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, . (17/22189-9, 17/02983-2, 17/25281-3, 16/09679-4, 17/21840-8)
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; et al. 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, . (17/19703-2, 17/11518-1, 17/02983-2, 17/18498-6)
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, . (17/16473-6, 16/20897-3, 16/02224-1, 17/02983-2, 17/17998-5)
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, . (18/14818-9, 17/02983-2, 13/07607-8)
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, . (17/02983-2)
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, . (16/20897-3, 17/21840-8, 17/02983-2)
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, . (16/20897-3, 17/21840-8, 17/02983-2, 16/02224-1)
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, . (17/16473-6, 17/02983-2)
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, . (14/50457-0, 18/04956-5, 17/02983-2)
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, . (15/10992-6, 14/11752-6, 17/02983-2)
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, . (14/11752-6, 13/25032-2, 17/02983-2)
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, . (17/02983-2, 17/16473-6)
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, . (17/04006-4, 16/09679-4, 17/02983-2)
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, . (16/09679-4, 16/20897-3, 17/02983-2)
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, . (13/07607-8, 17/02983-2)

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