MON-671 The Role of Glucocorticoid Receptor in Agrp Neurons in the Energy Balance

Abstract Disclosure: J. Gebenlian: None. J. Antunes-Rodrigues: None. L. Elias: None. Introduction: The arcuate nucleus of the hypothalamus (ARC) integrates hormonal and nutritional signals to regulate energy balance. AgRP/NPY neurons in the ARC are orexigenic and stimulated by fasting, whereas POMC neurons are anorexigenic and activated by feeding. Glucocorticoids (GCs), via glucocorticoid receptors (GR), increase food intake and body weight, and, as a counter regulator of insulin, play a role in the glucose homeostasis. Disbalance in these signals can lead to obesity and insulin resistance. However, the specific role of GR in AgRP neurons remains unclear. Aim: To investigate the role of the glucocorticoid receptor in AgRP neurons on the glucose and energy homeostasis. Methods: Conditional deletion of GR was generated using the cre-lox method, by breeding AgRP-iresCRE with GRflox/flox mice. Male and female AgRP(cre/+); GRflox/flox and control GRflox/flox mice were monitored to assess body weight, food intake, corticosterone levels, and VO₂ consumption and CO₂ production (OXYMAX CLAMS, Columbus) during the circadian cycle. Blood samples were collected at 8am and 5pm for the corticosterone measurement by radioimmunoassay. Glucose tolerance test (GTT), insulin tolerance test (ITT), body composition (Minispec Whole Body Composition Analyzer, Bruker), inguinal and retroperitoneal white adipose tissue, and interscapular brown adipose tissue (BAT) content were also investigated. BAT temperature was taken with a FLIR thermal camera. Results: AgRP-GR KO mice displayed no significant differences in body weight or food intake compared to respective controls over 10 weeks. Body composition analyses revealed comparable proportions of fat, fluid, and lean mass between genotypes in male and female mice. WAT depot weights (inguinal and retroperitoneal) were not different between groups. Metabolic cage studies showed similar VO₂ consumption and CO₂ production, in agreement with BAT thermogenesis results in both genotypes. GTT and ITT analyses demonstrated preserved glucose and insulin tolerance in AgRP(cre/+);GRflox/flox. Corticosterone measurements, in males, were not different, at 8am and 5pm, in both groups. Conclusion: Deletion of the glucocorticoid receptor in AgRP neurons is likely to not affect body weight, adiposity, food intake, glucose tolerance or insulin sensitivity, under basal conditions. Further study will be necessary to investigate the role of the glucocorticoid receptor in AgRP neurons on the metabolic responses and food intake under prolonged fasting. Funding: FAPESP, CNPq, CAPES, FAEPA Presentation: Monday, July 14, 2025