MON-681 Glucocorticoid Receptor Signaling in GABAergic Neurons Modulates Energy Balance in Male Mice

Abstract Disclosure: S.A. Pereira: None. A. Kim: None. A. Fontes: None. L. Arvizu-Sanchez: None. C.G. Meireles: None. D. Franssen: None. R.S. Carroll: None. U.B. Kaiser: None. V.M. Navarro: None. Background and Objectives: Glucocorticoids (GCs) are essential regulators of energy balance and metabolism. Excessive levels of GCs contribute to obesity, while a deficiency leads to anorexia and weight loss. GCs act on the central nervous system to modulate food intake and energy expenditure, thereby controlling body weight (BW); however, the precise mechanisms remain unclear. Previous studies from our group showed that deletion of leptin receptors in GABAergic neurons leads to obesity in mice, suggesting that GABAergic neurons serve as metabolic sensors to regulate BW. Notably, a significant proportion of GABAergic neurons express glucocorticoid receptors (GR). Therefore, in this study we aimed to investigate whether actions of GCs on metabolism occur through GR-expressing GABAergic neurons. Methods and Results: We generated mice with conditional deletion of GR in GABAergic neurons by crossing VgatCre mice with GRlox/lox mice to produce GABAGRKO mice. The BW of male GABAGRKO mice and their littermate controls (GRlox/lox) was monitored from the third week of life to age 16 weeks on a chow diet. Between ages 3 and 7 weeks, GABAGRKO males had similar BW to controls, but from ages 8 to 16 weeks, they weighed significantly less than controls. At age 16 weeks, we assessed daily food intake over a 7-day period, finding that GABAGRKO mice consumed less food compared to controls (p < 0.0001). In a separate experiment, adult GABAGRKO and control mice were fed a high-fat diet (HFD) for 20 days to induce obesity, followed by 15 days of treatment with corticosterone (CORT, 100 µg/mL in drinking water) or vehicle (V). BW and food intake were monitored throughout the experiment. After the 20-day HFD phase, both GABAGRKO and control mice showed similar daily food intake and BW gain. However, during the subsequent HFD + CORT treatment, GABAGRKO mice had significantly lower daily food intake (p < 0.0088) and gained less BW (p < 0.0001) compared to controls. CORT treatment increased daily food intake (p < 0.02) and BW (p < 0.003) in control mice compared to their V-treated controls, a response that was not observed in GABAGRKO mice compared to their V-treated littermates. Conclusions: The absence of GR in GABAergic neurons leads to reduced food intake and BW in GABAGRKO mice, both on a chow diet and when exposed to HFD with CORT treatment. Our data suggest that GCs acting on GR in GABAergic neurons play an important role in modulating food intake and BW regulation in male mice. These findings may provide new insights into the pathophysiology of obesity, particularly in conditions of elevated GC levels. Presentation: Monday, July 14, 2025