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 ARC neurons (POMCARC) 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 using DREADD technology (Receptors Designed Exclusively Designed by Activated Drugs) can restore corticosterone plasma levels in fasted animals; 3) To investigate the effects of chemogenetic manipulation of POMCARC on plasma corticosterone levels in LPS-treated mice; 4) To Determine whether POMCARC neurons modulate HPA axis activity via direct connections with CRF PVN neurons (CRFPVN) by optogenetics studies. 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 metabolic.
News published in Agência FAPESP Newsletter about the scholarship: