The somatotrophic axis as an essential regulator of neuroendocrine, metabolic and neurological aspects: from birth to senescence

• Grant number: 24/21641-9
• Support Opportunities: Research Projects - Thematic Grants
• Start date: October 01, 2025
• End date: September 30, 2030
• 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
• Pesquisadores principais: Renata Frazão
• Associated researchers: Davi José de Almeida Moraes ; Heraldo Mendes Garmes ; Licio Augusto Velloso ; Martin Andreas Metzger ; Raphael Escorsim Szawka

Abstract

The somatotrophic axis is composed of specific neural populations (including cells that express the neuropeptides somatostatin and growth hormone-releasing hormone - GHRH), pituitary cells that produce growth hormone (GH), and GH target cells, particularly hepatocytes, which are responsible for secreting insulin-like growth factor 1 (IGF-1) in response to variations in the pattern of GH secretion. It has been known for decades that this neuroendocrine axis is primarily responsible for regulating body growth, in addition to affecting cell development and proliferation, stimulating protein synthesis, and regulating glucose and lipid metabolism. However, alterations in this axis affect growth and development, insulin sensitivity, and body fat deposition. In addition, alterations in GH secretion profoundly impact longevity, aging, and predisposition to metabolic and neurodegenerative diseases. Since 2017, our research group has been leading studies investigating the involvement of the central nervous system (CNS) as a target of GH in order to regulate metabolic and neurological aspects. Among our main findings are 1) the detailed description of GH-responsive neurons in the CNS, 2) the role of GH in regulating food intake, energy expenditure, neuroendocrine adaptations, glucose homeostasis, and the action of ghrelin, through the presence of the GH receptor (GHR) in specific neural populations, 3) the action of GH in regulating anxiety and memory (spatial and fear), 4) the pro-inflammatory action of GHR signaling in the hypothalamus and 5) the redefinition of the main negative feedback loops that control GH secretion. Despite the great contribution of these findings, which have made us an international reference in the study of the central action of GH, many new questions have arisen from the findings of previous studies. It is worth noting that our focus has been on studying the action of GH in the CNS, although peripheral actions have also been investigated. Therefore, the main objective of this project is to unravel the importance of the somatotropic axis in regulating multiple neuroendocrine, metabolic, and neurological aspects. Due to its complexity and broad scope, this proposal was subdivided into 10 subprojects. Among the topics addressed in the proposed subprojects are: 1) Unraveling the physiological importance of the postnatal peak of GH secretion; 2) Understanding the mechanisms behind the maturation of the somatotropic axis at puberty and its relationship with the reproductive axis; 3) Unraveling new neural mechanisms of control of GH secretion, including the effect of GLP-1 (whose receptor is highly expressed in GHRH neurons), estrogens and specific neurotransmitters; 4) Identification of the GH pulse generator, through experiments using fiber photometry and Miniscope; 5) Understand the mechanisms related to the reduction in GH secretion in aging and obesity; 6) Identify new neural populations that mediate the effects of GH on metabolism, behavior and cognition; 7) Investigate how neurons expressing GHRH control the secretion of other pituitary hormones, in addition to GH (based on preliminary data that will be presented in the full proposal); 8) Unravel the mechanism of the pro-inflammatory action of GH on the CNS, the potential participation of glial cells and its impact on senescence, longevity and the emergence of neurodegenerative diseases; 9) Understand how the somatotropic axis can contribute to the development of some neurological and neurodevelopmental diseases; and 10) Evaluate the presence of part of the phenotypes observed in animal models in humans who present neuroendocrine dysfunctions of the somatotropic axis (e.g., GH deficiency or hypersecretion). (AU)