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Central nervous system as a target of growth hormone for the regulation of multiple biological functions

Grant number: 20/01318-8
Support Opportunities:Research Projects - Thematic Grants
Start date: October 01, 2020
End date: September 30, 2025
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Jose Donato Junior
Grantee:Jose Donato Junior
Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated researchers:Carlos Roberto Jorge Soares ; Carolina Demarchi Munhoz ; Martin Andreas Metzger ; Monica Roberto Gadelha ; Raphael Escorsim Szawka ; Renata Frazão
Associated research grant(s):24/07956-7 - Multi-user equipment approved in grant 20/01318-8: fiber photometry workstation, AP.EMU
Associated scholarship(s):24/21064-1 - Role of somatostatinergic neurons of the extended amygdala in the control of food intake, BP.DD
24/22859-8 - Role of insulin signaling on GHRH neurons in the alterations in GH secretion that occur in obesity, BP.PD
24/18534-6 - Importance of growth hormone receptor signaling in Nos1-expressing neurons, BP.PD
 + associated scholarships 24/05182-4 - Evaluation of the effects of GLP-1 receptor ablation in GH-releasing hormone-secreting neurons, BP.MS
24/03067-3 - Role of somatostatinergic neurons of the extended amygdala in the control of food intake, BP.DD
23/11833-5 - Physiological mechanisms that control GH secretion: identification of the pulse generator and events associated with somatotropic axis maturation, BP.DR
23/17012-3 - The importance of growth hormone (GH) action on the dorsomedial nucleus of the hypothalamus, BP.IC
20/15262-4 - Study of cellular factors that affects energy balance through AgRP neurons: role of connexin 43 and mTORC1 pathway, BP.DR
22/11145-9 - Evaluation of metabolic alterations in animals with GH receptor ablation in specific neural populations, BP.IC
21/03316-5 - Evaluation of the importance of GABAergic and dopaminergic transmission in neurons that express the growth hormone-releasing hormone to the control of GH secretion, BP.PD - associated scholarships

Abstract

The growth hormone (GH) is secreted by the anterior pituitary gland and is related to the regulation of several important physiological functions, such as cell proliferation, tissue growth, protein synthesis, carbohydrate and lipid metabolism, among others. Classically, the main target tissues of GH are the liver, skeletal muscle, bones and adipose tissue which, taken as a whole, were believed to be responsible for the main biological effects of this hormone. However, recent evidence has indicated that the central nervous system (CNS) is also a critical target tissue for many of the biological functions of GH which include regulation of metabolism, control of several cognitive functions, behavior modulation, neurotrophic action, among others. Part of this scientific evidence was discovered by our research group, which is currently considered a world leader in the study of the action of GH on the CNS. These works received the financial support from FAPESP, through the Thematic Project entitled: "Action of growth hormone on the nervous system: relevance to neural functions and disease", which ends in July 2020. This proposal aims to continue the successful previous Project that has resulted, to date, in more than 16 scientific publications on the action of GH or its main intracellular signaling pathway, which involves STAT5, on the CNS. For this Grant, we propose a broad set of 19 subprojects that will use at least 17 genetically modified mouse models, together with in vivo injection of viral vectors and pharmacological experiments in animal models, as well as dosages in humans, in order to obtain more details on the mechanisms of action and the possible functions regulated by the GH through its direct action on the CNS. Our goal is to redefine the mechanisms of action of GH, including the CNS as an important target of this hormone for the regulation of multiple biological functions. (AU)

Articles published in Agência FAPESP Newsletter about the research grant:
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Scientific publications (34)
(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)
DONATO, JR., JOSE; WASINSKI, FREDERICK; FURIGO, ISADORA C.; METZGER, MARTIN; FRAZAO, RENATA. Central Regulation of Metabolism by Growth Hormone. CELLS, v. 10, n. 1, . (20/01318-8, 16/09679-4, 19/21707-1, 16/20897-3, 17/16473-6)
DOS SANTOS, WILLIAN O.; WASINSKI, FREDERICK; TAVARES, MARIANA R.; CAMPOS, ANA M. P.; ELIAS, CAROL F.; LIST, EDWARD O.; KOPCHICK, JOHN J.; SZAWKA, RAPHAEL E.; DONATO JR, JOSE. Ablation of Growth Hormone Receptor in GABAergic Neurons Leads to Increased Pulsatile Growth Hormone Secretion. Endocrinology, v. 163, n. 8, p. 17-pg., . (16/20897-3, 20/01318-8, 20/10102-9)
DOS SANTOS, WILLIAN O.; GUSMAO, DANIELA O.; WASINSKI, FREDERICK; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO, JR., JOSE. Effects of Growth Hormone Receptor Ablation in Corticotropin-Releasing Hormone Cells. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 22, n. 18, . (21/03316-5, 16/20897-3, 20/01318-8)
GUSMAO, DANIELA O.; DE SOUSA, MARIA E.; DE SOUSA, LIGIA M. M.; SILVA, JOSIANE N.; FRAZAO, RENATA; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO JR, JOSE. GH-Releasing Hormone Neurons Regulate the Hypothalamic-Pituitary-Somatotropic Axis via Short-Loop Negative Feedback. Endocrinology, v. 166, n. 5, p. 14-pg., . (20/01318-8, 21/11551-4, 22/11262-5, 21/03316-5, 23/11833-5)
GUSMAO, DANIELA O.; DE SOUSA, LIGIA M. M.; DE SOUSA, MARIA E.; RUSEW, STEPHANIE J. R.; LIST, EDWARD O.; KOPCHICK, JOHN J.; GOMES, ANDRE F.; CAMPIDELI-SANTANA, ANA C.; SZAWKA, RAPHAEL E.; DONATO JR, JOSE. Characterization and Regulation of the Neonatal Growth Hormone Surge. Endocrinology, v. 165, n. 12, p. 12-pg., . (21/03316-5, 23/11833-5, 24/03067-3, 20/01318-8)
MANSANO, NAIRA DA SILVA; VIEIRA, HENRIQUE RODRIGUES; ARAUJO-LOPES, ROBERTA; SZAWKA, RAPHAEL ESCORSIM; DONATO JR, JOSE; FRAZAO, RENATA. Fasting Modulates GABAergic Synaptic Transmission to Arcuate Kisspeptin Neurons in Female Mice. Endocrinology, v. 164, n. 11, p. 14-pg., . (17/22189-9, 19/21707-1, 20/01318-8)
DE SOUZA, GABRIEL O.; DOS SANTOS, WILLIAN O.; DONATO, JOSE. Ironing out obesity. TRENDS IN ENDOCRINOLOGY AND METABOLISM, v. 35, n. 6, p. 3-pg., . (20/15262-4, 20/01318-8)
WASINSKI, FREDERICK; BARRILE, FRANCO; PEDROSO, JOAO A. B.; QUARESMA, PAULA G. F.; DOS SANTOS, WILLIAN O.; LIST, EDWARD O.; KOPCHICK, JOHN J.; PERELLO, MARIO; DONATO, JR., JOSE. Ghrelin-induced Food Intake, but not GH Secretion, Requires the Expression of the GH Receptor in the Brain of Male Mice. Endocrinology, v. 162, n. 7, . (20/01318-8, 16/20897-3, 17/25281-3)
WASINSKI, FREDERICK; TEIXEIRA, PRYSCILA D. S.; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO JR, JOSE. Growth hormone receptor contributes to the activation of STAT5 in the hypothalamus of pregnant mice. Neuroscience Letters, v. 770, . (20/01318-8, 16/20897-3)
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; TAVARES, MARIANA R.; GUSMAO, DANIELA O.; LIST, EDWARD O.; KOPCHICK, JOHN J.; ALVES, GUILHERME A.; FRAZAO, RENATA; DONATO JR, JOSE. Central growth hormone action regulates neuroglial and proinflammatory markers in the hypothalamus of male mice. Neuroscience Letters, v. 806, p. 8-pg., . (19/21707-1, 19/07005-4, 20/10102-9, 20/01318-8, 21/03316-5)
DE SOUZA, GABRIEL O.; CHAVES, FERNANDA M.; SILVA, JOSIANE N.; PEDROSO, JOAO A. B.; METZGER, MARTIN; FRAZAO, RENATA; DONATO JR, JOSE. Gap junctions regulate the activity of AgRP neurons and diet-induced obesity in male mice. Journal of Endocrinology, v. 255, n. 2, p. 16-pg., . (21/11551-4, 19/21707-1, 17/21854-9, 20/01318-8, 17/16473-6)
NOGUEIRA, PEDRO A. S.; MOURA-ASSIS, ALEXANDRE; ZANESCO, ARIANE M.; BOMBASSARO, BRUNA; GALLO-FERRAZ, ANA L.; SIMOES, MARCELA R.; ENGEL, DAIANE F.; RAZOLLI, DANIELA S.; GASPAR, JOANA M.; DONATO JUNIOR, JOSE; et al. The orphan G protein-coupled receptor, GPR139, is expressed in the hypothalamus and is involved in the regulation of body mass, blood glucose, and insulin. Neuroscience Letters, v. 792, p. 8-pg., . (20/01318-8, 13/07607-8, 18/14818-9)
VELLOSO, LICIO A.; DONATO, JOSE. Growth Hormone, Hypothalamic Inflammation, and Aging. JOURNAL OF OBESITY & METABOLIC SYNDROME, v. 33, n. 4, p. 12-pg., . (13/07607-8, 20/01318-8)
TAVARES, MARIANA R.; DOS SANTOS, WILLIAN O.; AMARAL, ANDRESSA G.; LIST, EDWARD O.; KOPCHICK, JOHN J.; ALVES, GUILHERME A.; FRAZAO, RENATA; DOS SANTOS, JESSICA D. M.; CRUZ, ALESSANDRA G.; CAMPOREZ, JOAO PAULO; et al. Growth hormone receptor in VGLUT2 or Sim1 cells regulates glycemia and insulin sensitivity. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, v. 121, n. 52, p. 11-pg., . (20/10102-9, 21/08792-0, 18/04956-5, 22/11262-5, 20/01318-8)
TAVARES, MARIANA R.; WASINSKI, FREDERICK; METZGER, MARTIN; DONATO JR, JOSE. Impact of Growth Hormone on Microglial and Astrocytic Function. JOURNAL OF INTEGRATIVE NEUROSCIENCE, v. 23, n. 2, p. 8-pg., . (19/07005-4, 20/10102-9, 17/16473-6, 20/01318-8)
DONATO, JOSE, JR.. Programming of metabolism by adipokines during development. NATURE REVIEWS ENDOCRINOLOGY, v. 19, n. 7, p. 13-pg., . (20/01318-8)
DE SOUSA, MARIA E.; GUSMAO, DANIELA O.; DOS SANTOS, WILLIAN O.; MORIYA, HENRIQUE T.; DE LIMA, FELIPE F.; LIST, EDWARD O.; KOPCHICK, JOHN J.; DONATO JR, JOSE. Fasting and prolonged food restriction differentially affect GH secretion independently of GH receptor signaling in AgRP neurons. Journal of Neuroendocrinology, v. N/A, p. 14-pg., . (21/03316-5, 20/01318-8)
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)
DE SOUZA, GABRIEL O.; WASINSKI, FREDERICK; DONATO, JOSE. Characterization of the metabolic differences between male and female C57BL/6 mice. Life Sciences, v. 301, p. 13-pg., . (20/01318-8, 16/20897-3)
GUSMAO, DANIELA O.; DE SOUSA, MARIA E.; TAVARES, MARIANA R.; DONATO, JOSE. Increased GH Secretion and Body Growth in Mice Carrying Ablation of IGF-1 Receptor in GH-releasing Hormone Cells. Endocrinology, v. 163, n. 11, p. 13-pg., . (20/10102-9, 21/03316-5, 20/01318-8)
BOHLEN, TABATA M.; DE PAULA, DANIELLA G.; TEIXEIRA, PRYSCILA D. S.; MANSANO, NAIRA DA SILVA; ALVES, GUILHERME ANDRADE; DONATO JR, JOSE; FRAZAO, RENATA. Socs3 ablation in kisspeptin cells partially prevents lipopolysaccharide-induced body weight loss. CYTOKINE, v. 158, p. 9-pg., . (15/14588-5, 19/21707-1, 20/01318-8, 13/00801-3, 16/03082-6, 17/22189-9)
MOINHO, TAIS M.; TAVARES, MARIANA R.; CAMPOS, ANA M. P.; FRAZAO, RENATA; METZGER, MARTIN; DONATO, JOSE, JR.. Simple method to induce denaturation of fluorescent proteins in free-floating brain slices. JOURNAL OF NEUROSCIENCE METHODS, v. 371, p. 10-pg., . (19/21707-1, 20/01318-8, 20/10102-9, 17/16473-6)
CHAVES, FERNANDA M.; WASINSKI, FREDERICK; TAVARES, MARIANA R.; MANSANO, NAIRA S.; FRAZAO, RENATA; GUSMAO, DANIELA O.; QUARESMA, PAULA G. F.; PEDROSO, JOAO A. B.; ELIAS, CAROL F.; LIST, EDWARD O.; et al. Effects of the Isolated and Combined Ablation of Growth Hormone and IGF-1 Receptors in Somatostatin Neurons. Endocrinology, v. 163, n. 5, p. 13-pg., . (16/20897-3, 17/25281-3, 20/01318-8, 20/10102-9, 19/21707-1, 17/21854-9, 17/22189-9, 21/03316-5)
SILVA, TALITA M.; WASINSKI, FREDERICK; FLOR, KARINE C.; LIST, EDWARD O.; KOPCHICK, JOHN J.; TAKAKURA, ANA C.; DONATO JR, JOSE; MOREIRA, THIAGO S.. The effect of central growth hormone action on hypoxia ventilatory response in conscious mice. Brain Research, v. 1791, p. 10-pg., . (16/20897-3, 20/01318-8, 15/23376-1, 18/13707-9)
SOUZA, RUDIERI; BUENO, DEBORA; LIMA, LEANDRO B.; MUCHON, MARIA J.; GONCALVES, LUCIANO; DONATO, JOSE, JR.; SHAMMAH-LAGNADO, SARA J.; METZGER, MARTIN. Top-down projections of the prefrontal cortex to the ventral tegmental area, laterodorsal tegmental nucleus, and median raphe nucleus. Brain Structure & Function, v. 227, n. 7, p. 23-pg., . (20/01318-8, 17/16473-6)
GUSMAO, DANIELA O.; VIEIRA, HENRIQUE R.; MANSANO, NAIRA S.; TAVARES, MARIANA R.; DE SOUSA, LIGIA M. M.; WASINSKI, FREDERICK; FRAZAO, RENATA; DONATO JR, JOSE. Pattern of gonadotropin secretion along the estrous cycle of C57BL/6 female mice. PHYSIOLOGICAL REPORTS, v. 10, n. 17, p. 18-pg., . (16/20897-3, 20/01318-8, 20/10102-9, 19/21707-1, 17/22189-9, 21/03316-5)
PAULA, DANIELLA G. DE; BOHLEN, TABATA M.; ZAMPIERI, THAIS TESSARI; MANSANO, NAIRA S.; VIEIRA, HENRIQUE R.; GUSMAO, DANIELA O.; WASINSKI, FREDERICK; DONATO JR, JOSE; FRAZAO, RENATA. Distinct effects of growth hormone deficiency and disruption of hypothalamic kisspeptin system on reproduction of male mice. Life Sciences, v. 285, . (20/01318-8, 16/03082-6, 21/03316-5, 16/20897-3, 15/20198-5, 13/07908-8, 15/14588-5, 17/22189-9)
QUARESMA, PAULA G. F.; WASINSKI, FREDERICK; MANSANO, NAIRA S.; FURIGO, ISADORA C.; TEIXEIRA, PRYSCILA D. S.; GUSMAO, DANIELA O.; FRAZAO, RENATA; DONATO JR, JOSE. Leptin Receptor Expression in GABAergic Cells is Not Sufficient to Normalize Metabolism and Reproduction in Mice. Endocrinology, v. 162, n. 11, . (21/03316-5, 16/09679-4, 19/21707-1, 17/25281-3, 20/01318-8, 17/22189-9, 16/20897-3)
DONATO JR, JOSE; KOPCHICK, JOHN J.. New findings on brain actions of growth hormone and potential clinical implications. REVIEWS IN ENDOCRINE & METABOLIC DISORDERS, v. 25, n. 3, p. 13-pg., . (20/01318-8)
TAVARES, MARIANA ROSOLEN; FRAZAO, RENATA; DONATO JR, JOSE. Understanding the role of growth hormone in situations of metabolic stress. Journal of Endocrinology, v. 256, n. 1, p. 11-pg., . (19/21707-1, 20/10102-9, 20/01318-8)
MENEZES, FILIPE; WASINSKI, FREDERICK; DE SOUZA, GABRIEL O.; NUNES, AMANDA P.; BERNARDES, EMERSON S.; DOS SANTOS, SOFIA N.; DA SILVA, FABIO F. A.; PERONI, CIBELE N.; OLIVEIRA, JOAO E.; KOPCHICK, JOHN J.; et al. The Pattern of GH Action in the Mouse Brain. Endocrinology, v. 165, n. 7, p. 16-pg., . (16/20897-3, 20/10435-8, 20/01318-8)
DOS SANTOS, WILLIAN O.; JULIANO, VITOR A. L.; CHAVES, FERNANDA M.; VIEIRA, HENRIQUE R.; FRAZAO, RENATA; LIST, EDWARD O.; KOPCHICK, JOHN J.; MUNHOZ, CAROLINA D.; DONATO, JOSE, JR.. Growth Hormone Action in Somatostatin Neurons Regulates Anxiety and Fear Memory. JOURNAL OF NEUROSCIENCE, v. 43, n. 40, p. 14-pg., . (20/01318-8, 17/21854-9, 19/21707-1)
FERNANDES, CAROLINE; FORNY-GERMANO, LETICIA; ANDRADE, MAYARA M.; LYRA E SILVA, NATALIA M.; RAMOS-LOBO, ANGELA M.; MEIRELES, FERNANDA; TOVAR-MOLL, FERNANDA; HOUZEL, JEAN CHRISTOPHE; DONATO JR, JOSE; DE FELICE, FERNANDA G.. Leptin receptor reactivation restores brain function in early-life Lepr-deficient mice. BRAIN, v. 147, n. 8, p. 12-pg., . (20/01318-8)