Role of orexin neurons as mediators of the central effects induced by growth hormone

• Grant number: 16/20897-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Effective date (Start): January 01, 2017
• Effective date (End): December 31, 2019
• Field of knowledge: Biological Sciences - Physiology
• Acordo de Cooperação: Coordination of Improvement of Higher Education Personnel (CAPES)
• Principal Investigator: Jose Donato Junior
• Grantee: Frederick Wasinski
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil

Abstract

Orexins, also known as hypocretin, neuropeptides are responsible for regulating arousal, wakefulness, appetite, blood sugar control, and other physiological processes. They are found in neurons of the lateral hypothalamus and have neuroexcitatory effects. The lack of orexin in the brain is associated with narcolepsy in humans and animals, thus indicating its importance in the sleep-wake control. Interestingly, the growth hormone (GH) also modulates various biological functions controlled by orexins neurons. For example, GH-deficient individuals have severe metabolic disorders, such as sleep disturbance, hyperphagia, changes in glycemic control, obesity, among others. They feature changes in attention, wakefulness and sleep. However, a possible interaction between GH and orexin has never been directly studied. Thus, in this project, we formulated a hypothesis that GH may act directly on the orexin neurons, supporting neuroanatomical for many of the dysfunctions presented in GH deficiency, mediating the change in the functioning of orexin neurons. To investigate a possible interrelationship between GH and orexin neurons, we use mice that have GH receptor deficiency only in orexin neurons (GHR flox / flox orexin Cre). In this way, we can study the effects of GH exclusively on these neurons without affecting other cell populations with the GH receptor. The evolution of the weight of these animals will be monitored until adulthood, when they will be housed in individual boxes and tested for metabolic assessment, glucose and food intake. Subgroups will be subjected to food restriction and exercise along with its controls to study physiological situations in which GH secretion is high. From these experiments, we hope to better understand the mechanics involved in the communication between growth hormone and orexins neurons. Our data has the potential to identify the specific neuronal circuit involved in many of the effects of GH. (AU)

Scientific publications

(28)

(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)

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, MAR 2021. (18/04956-5, 17/02983-2, 20/01318-8, 17/21840-8, 16/20897-3, 17/21854-9, 17/22189-9)

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. (17/02983-2, 16/20897-3)

TEIXEIRA, PRYSCILA D. S.; RAMOS-LOBO, ANGELA M.; TAVARES, MARIANA ROSOLEN; WASINSKI, FREDERICK; FRAZAO, RENATA; DONATO JR, JOSE. Characterization of the onset of leptin effects on the regulation of energy balance. Journal of Endocrinology, v. 249, n. 3, p. 239-251, JUN 2021. (14/11752-6, 16/20897-3, 17/21840-8, 20/10102-9)

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. (16/20897-3, 14/11752-6, 17/02983-2, 16/09679-4)

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, NOV 15 2021. (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, NOV 2021. (21/03316-5, 16/09679-4, 19/21707-1, 17/25281-3, 20/01318-8, 17/22189-9, 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, OCT 15 2020. (17/02983-2, 17/25281-3, 16/20897-3)

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. (16/20897-3, 17/02983-2, 16/09679-4)

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, JUN 2018. (16/20897-3, 14/11752-6, 12/02388-3, 16/09679-4, 15/10992-6, 17/02983-2, 12/24345-4)

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. (16/20897-3, 16/09679-4, 17/04006-4, 17/02983-2, 17/21840-8, 17/25281-3)

RAMOS-LOBO, ANGELA M.; FURIGO, ISADORA C.; TEIXEIRA, PRYSCILA D. S.; ZAMPIERI, THAIS T.; WASINSKI, FREDERICK; BUONFIGLIO, DANIELLA C.; DONATO, JR., JOSE. Maternal metabolic adaptations are necessary for normal offspring growth and brain development. PHYSIOLOGICAL REPORTS, v. 6, n. 5, MAR 2018. (16/20897-3, 12/15517-6, 15/10992-6, 14/11752-6)

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., 2022-05-13. (20/01318-8, 16/20897-3)

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., 2022-05-01. (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., 2022-07-01. (16/20897-3, 20/01318-8, 15/23376-1, 18/13707-9)

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., 2022-09-01. (16/20897-3, 20/01318-8, 20/10102-9, 19/21707-1, 17/22189-9, 21/03316-5)

CAMPOS, ANA M. P.; TEIXEIRA, PRYSCILA D. S.; WASINSKI, FREDERICK; KLEIN, MARIANNE O.; BITTENCOURT, JACKSON C.; METZGER, MARTIN; DONATO, JOSE, JR.. 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, v. 32, n. 9, p. 11-pg., 2020-08-24. (16/02224-1, 17/17998-5, 16/20897-3, 17/02983-2, 17/16473-6)

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. (16/20897-3, 16/02224-1, 17/16473-6, 17/17998-5, 17/02983-2)

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. (16/20897-3, 16/02224-1, 17/16473-6, 17/02983-2, 17/17998-5)

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, JUL 2021. (20/01318-8, 16/20897-3, 17/25281-3)

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, SEP 2021. (21/03316-5, 16/20897-3, 20/01318-8)

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. (17/02983-2, 16/20897-3, 17/25281-3, 17/16473-6)

CAMPOS, ANA M. P.; WASINSKI, FREDERICK; KLEIN, MARIANNE O.; BITTENCOURT, JACKSON C.; METZGER, MARTIN; DONATO JR, JOSE. Fasting reduces the number of TRH immunoreactive neurons in the hypothalamic paraventricular nucleus of male rats, but not in mice. Neuroscience Letters, v. 752, MAY 1 2021. (16/02224-1, 17/16473-6, 17/17998-5, 16/20897-3)

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. (16/20897-3, 17/02983-2, 16/09679-4)

DONATO, JR., JOSE; WASINSKI, FREDERICK; FURIGO, ISADORA C.; METZGER, MARTIN; FRAZAO, RENATA. Central Regulation of Metabolism by Growth Hormone. CELLS, v. 10, n. 1, JAN 2021. (20/01318-8, 16/09679-4, 19/21707-1, 16/20897-3, 17/16473-6)

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, 2020-01-10. (16/20897-3, 17/21840-8, 17/02983-2)

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, JAN 23 2022. (20/01318-8, 16/20897-3)

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., 2022-08-01. (16/20897-3, 20/01318-8, 20/10102-9)

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. (16/20897-3, 17/21840-8, 17/02983-2, 16/02224-1)