Hypothalamic neuronal circuitry and phenotypes involved in the coupling of hypothalamic-pituitary-adrenal axis activity to changes in the energy homeostasis

• Grant number: 16/17968-6
• Support Opportunities: Research Grants - Young Investigators Grants
• Start date: October 01, 2017
• End date: September 30, 2022
• Field of knowledge: Biological Sciences - Physiology - Physiology of Organs and Systems
• Principal Investigator: Rodrigo César Rorato
• Grantee: Rodrigo César Rorato
• Host Institution: Escola Paulista de Medicina (EPM). Universidade Federal de São Paulo (UNIFESP). Campus São Paulo. São Paulo , SP, Brazil
• Associated researchers: Adelino Sanchez Ramos da Silva ; Lucila Leico Kagohara Elias ; Renê de Oliveira Beleboni ; Suzelei de Castro França
• Associated scholarship(s): 20/11612-0 - Role of POMC neurons in the reduction of plasma corticosterone levels after exogenous leptin replacement in fasted animals, BP.IC; 20/07413-2 - Effects of selective LepR deletion in AgRP / NPYARC neurons on the activity of the hypothalamus-pituitary-adrenal axis in fasted mice, BP.IC; 19/17095-0 - Necessity and sufficiency of leptin signaling in POMCARC neurons for HPA axis activity suppression during fasting-induced stress, BP.IC; + associated scholarships 18/23362-9 - Effects of leptin signaling modulation in AgRP/NPYARC neurons on hypothalamic-pituitary-adrenal axis control in fasted mice, BP.IC; 18/18359-9 - Role of POMCARC neurons in the HPA axis hiperactivity during fasting-induced stress, BP.MS; 18/06871-7 - Necessity and sufficiency of leptin signaling in POMCARC neurons for HPA axis activity suppression during fasting-induced stress, BP.IC; 17/22335-5 - Hypothalamic neuronal circuitry and phenotypes involved in the coupling of hypothalamic-pituitary-adrenal axis activity to changes in the energy homeostasis, BP.TT; 17/20190-0 - Hypothalamic neuronal circuitry and phenotypes involved in the coupling of Hypothalamic-Pituitary-Adrenal axis activity to changes in the Energy Homeostasis., BP.JP - associated scholarships

Abstract

The increased number of individuals exhibiting obesity and Metabolic Syndrome has been associated with prolonged stress caused by modern life demands. There are studies suggesting that Hypothalamic-Pituitary-Adrenal (HPA) axis hyperactivation could account for these conditions, since the end product of this axis, the glucocorticoid, has important adipogenic actions. Interestingly, it has been suggested that HPA axis activation is coupled to changes in peripheral energy stores. Indeed, during fasting or Type 1 Diabetes paradigm the adrenal axis hyperactivity induced by the metabolic stress can be reverted by exogenous leptin replacement. On the other hand, hyperleptinemic obese animals are hyporesponsive to leptin actions, suggesting that a failure in the signaling of this hormone could contribute to the HPA axis hyperactivity. However, the neurocircuitry and the neuronal phenotypes involved in this coupling are unknown. Considering the high Leptin Receptor expression (LepR) in ARC neurons and the huge number of inputs that PVN neurons receive from the ARC, this study aims: 1) to determine the necessity and sufficiency of leptin signaling in POMC and AgRP/NPY ARC neurons (POMCARC and AgRP/NPYARC) to corticosterone secretion under metabolic challenge (fasting) using conditional gene edition using the Cre-LoxP system; 2) to investigate whether selective and specific neuronal activity manipulation of POMCARC and AgRP/NPYARC using DREADD technology (Receptors Designed Exclusively Designed by Activated Drugs) can restore corticosterone plasma levels in fasted animals; 3) to determine whether POMCARC and AgRP/NPYARC neurons modulate HPA axis activity via direct connections with CRF PVN neurons (CRFPVN) by optogenetics studies and 4) to analyze monosynaptics connections between LepR positive neurons, expressed outside the ARC, and CRFPVN neurons using cre-dependent helper virus system. Our study will permit us to identify the neuronal subsets and the neurocircuitry involved in the adrenal axis regulation during nutritional stress and may contribute to the recognition of new and specific therapeutic targets important to the treatment of disorders associated with energetic homeostasis. In addition, our proposal will allow to establish new field research and to disseminate state-of-the-art tools used in neuroscience in the hosting and partner institutions and will also contribute to the exchange with Beth Israel Deaconess Medical Center - Harvard Medical School. (AU)

Scientific publications

(5)

(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)

TRUJILLO, VERONICA; VALENTIM-LIMA, EVANDRO; MENCALHA, RODRIGO; CARBALAN, QUEZIA S. R.; DOS-SANTOS, RAONI C.; FELINTRO, VIVIANE; GIRARDI, CARLOS E. N.; RORATO, RODRIGO; LUSTRINO, DANILO; REIS, LUIS C.; et al. Neonatal Serotonin Depletion Induces Hyperactivity and Anxiolytic-like Sex-Dependent Effects in Adult Rats. Molecular Neurobiology, v. 58, n. 3, p. 1036-1051, MAR 2021. (16/17968-6)

OLIVEIRA, LUCIANA DA COSTA; MORAIS, GUSTAVO PAROSCHI; DE OLIVEIRA, FRANCIANE PEREIRA; MATA, MILENE MONTAVONI; VERAS, ALLICE SANTOS CRUZ; DA ROCHA, ALISSON LUIZ; ELIAS, LUCILA LEICO KAGOHARA; TEIXEIRA, GIOVANA RAMPAZZO; DE MORAES, CAMILA; CINTRA, DENNYS E.; et al. Intermittent fasting combined with exercise training reduces body mass and alleviates hypothalamic disorders induced by high-fat diet intake. JOURNAL OF NUTRITIONAL BIOCHEMISTRY, v. 119, p. 12-pg., 2023-05-29. (16/17968-6, 20/08192-0, 19/17532-1, 17/25492-4, 19/21709-4, 21/06291-3)

ALVES FERNANDES, ALAN CARLOS; DE OLIVEIRA, FRANCIANE PEREIRA; FERNANDEZ, GIMENA; VIEIRA, LUANE DA GUIA; ROSA, CRISTIANE GUGELMIN; DO NASCIMENTO, TAIS; FRANCA, SUZELEI DE CASTRO; DONATO JR, JOSE; VELLA, KRISTEN R.; ANTUNES-RODRIGUES, JOSE; et al. Arcuate AgRP, but not POMC neurons, modulate paraventricular CRF synthesis and release in response to fasting. CELL AND BIOSCIENCE, v. 12, n. 1, p. 14-pg., 2022-07-28. (16/17968-6, 19/27581-0)

ZIMERMAN, JEANINI; NINO, OSCAR M. S.; DA COSTA, CHARLES S.; ZANOL, JORDANA F.; COMERIO, MILENA; DE SOUZA, LETICIA N. DA GAMA; MIRANDA-ALVES, LEANDRO; MIRANDA, ROSIANE A.; LISBOA, PATRICIA C.; CAMILO, TAYS A.; et al. Subacute high-refined carbohydrate diet leads to abnormal reproductive control of the hypothalamic-pituitary axis in female rats. REPRODUCTIVE TOXICOLOGY, v. 119, p. 13-pg., 2023-05-29. (16/17968-6, 19/21707-1)

RORATO, RODRIGO; FERREIRA, NATHALIA L.; OLIVEIRA, FRANCIANE P.; FIDELES, HIGOR J.; CAMILO, TAYS A.; ANTUNES-RODRIGUES, JOSE; MECAWI, ANDRE S.; ELIAS, LUCILA L. K.. Prolonged Activation of Brain CB2 Signaling Modulates Hypothalamic Microgliosis and Astrogliosis in High Fat Diet-Fed Mice. INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v. 23, n. 10, p. 15-pg., 2022-05-01. (16/17968-6, 19/27581-0, 20/11612-0, 14/20704-5, 18/18071-5)