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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 type:Research Grants - Young Investigators Grants
Duration: October 01, 2017 - September 30, 2021
Field of knowledge:Biological Sciences - Physiology
Principal Investigator:Rodrigo César Rorato
Grantee:Rodrigo César Rorato
Home Institution: Universidade de Ribeirão Preto (UNAERP). Campus Ribeirão Preto. Ribeirão Preto , SP, Brazil
Assoc. researchers:Adelino Sanchez Ramos da Silva ; Lucila Leico Kagohara Elias ; Renê de Oliveira Beleboni ; Suzelei de Castro França
Associated scholarship(s):19/17095-0 - Necessity and sufficiency of leptin signaling in POMCARC neurons for HPA axis activity suppression during fasting-induced stress, BP.IC
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
17/20190-0 - Hypothalamic neuronal circuitry and phenotypes involved in the coupling of hypothalamic-pituitary-adrenal axis activity to changes in the energy homeostasis, BP.JP

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)