Growth hormone signaling in the brain as a mediator of puberty and fertility

• Grant number: 17/21840-8
• Support Opportunities: Regular Research Grants
• Start date: February 01, 2018
• End date: January 31, 2020
• Field of knowledge: Biological Sciences - Physiology
• Principal Investigator: Renata Frazão
• Grantee: Renata Frazão
• Host Institution: Instituto de Ciências Biomédicas (ICB). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Associated researchers: Jose Donato Junior
• Associated scholarship(s): 19/05364-7 - Genetic mice models care, BP.TT

Abstract

Growth hormone (GH) is an important factor involved in the regulation of multiple biological functions. However, although the influence of GH is widespread throughout several organs and tissues, the effects of GH on brain functions such as those related to reproductive functions are still elusive. GH deficiency or resistance can be related to late puberty onset, lack of sexual maturation and infertility. In contrast, GH therapy can accelerate puberty onset or be used to increase pregnancy rates in woman treating fertility related problems. Suggesting, that GH can modulate reproduction. However, the molecular and cellular mechanisms by which GH could potentially modulate the reproductive system are not fully understood. We present conclusive evidence demonstrating that GH has a direct effect on areas of interest in the nervous system, either by identifying the main pathway recruited after GH receptor activation (STAT5) or by demonstrating preliminary results showing that human GH can modulate ion channels to induce rapid effects on hypothalamic neurons resting membrane potential. Indicating that the brain is a potentially important GH-target tissue. Based on the preliminary results presented, our goal is to understand whether GH signaling in the brain is required to sexual maturation and maintenance of reproductive functions. For this purpose, we will use the Cre-LoxP technology to induce GH receptor deletion in specific neuronal populations (kiss1-Cre, leptin receptor-Cre) or globally in the brain (Nestin-Cre model). We will be able to identify whether there is a specific population in which this hormone can direct act to modulate the HPG axis. Moreover, using the whole-cell path-clamp recordings in brain slices, we will complement the investigation regarding the effects of exogenous GH (human and mouse) on the biophysical properties of different hypothalamic populations. The proposed research has the potential to contribute significantly to the literature, demonstrating whether GH acts as a signal in the hypothalamus to modulate events that culminate in sexual maturation and in the maintenance of reproductive functions. (AU)

Scientific publications

(8)

(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)

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)

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, FEB 8 2019. (16/09679-4, 17/16473-6, 17/05007-4, 17/04006-4, 17/02983-2, 17/21840-8)

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)

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. (20/01318-8, 17/21840-8, 17/22189-9, 17/21854-9, 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, DEC 2019. (16/20897-3, 17/21840-8, 17/02983-2, 16/02224-1)

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. (17/22189-9, 17/02983-2, 17/25281-3, 16/09679-4, 17/21840-8)

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