SAT-037 Sex- and Age-Dependent Regulation of the Glucose Receptor Adgrl1 in Mice

Abstract Disclosure: T. Emtiaz: None. N. Hasan: None. M.T. Otunla: None. N. Rashid: None. M. Hodges: None. K.H. Chhabra: None. Introduction: We recently identified adhesion G-protein coupled receptor L1(Adgrl1) as a glucose receptor that is essential for controlling glucose and energy balance. Deletion of Adgrl1 in the hypothalamus causes obesity in a sex-specific manner in mice. While hypothalamus-specific knockout (KO) of Adgrl1 in male mice causes obesity, ovary-intact female mice have normal body weight even after the hypothalamic Adgrl1 deficiency. Interestingly, ovariectomy unmasks the effects of hypothalamus-specific Adgrl1 deficiency in female mice, indicating sex-dependent regulation by hypothalamic Adgrl1. Therefore, in this study, we determined the role of estrogens on Adgrl1 expression, specifically in the hypothalamus in young and relatively older female mice. Methods: We first determined hypothalamic Adgrl1 expression in 8- and 24-week-old male and female C57BL/6J mice. We also measured Adgrl1 expression in the ovaries of 8-week-old female mice and compared the expression with that observed in the hypothalamus. Then, we treated a separate cohort of 8-week-old female mice with 17b-estradiol (E2, 1 mg/Kg, intraperitoneally) and measured their hypothalamic Adgrl1. In addition, we excised ovaries from another group of 8-week-old female mice (OVX-group), and three weeks later, we collected their hypothalamus to measure Adgrl1 expression by qPCR. Finally, to determine whether Adgrl1 and estrogen receptors are co-expressed in the mouse hypothalamus, we used RNA fluorescence in situ hybridization to detect their RNA in the ventromedial nucleus of the hypothalamus (VMH). Result: The qPCR analysis confirmed the expression of Adgrl1 in the mouse ovary, which was about 60% of that present in the hypothalamus. Moreover, female mice had higher (male, 100.0 ±10.8 vs female, 144.3 ±8.7, p<.05) Adgrl1 expression in the hypothalamus than male mice at 8 weeks of age. Hypothalamic Adgrl1 was reduced with age in both male and female mice (male, 100 ±11.33 vs 43.90 ±5.1;female, 100 ±6.6 vs 80.41 ±7.1, 8 vs 24 weeks, p<0.05). E2 administration decreased hypothalamic Adgrl1 expression (exp, 51.67 ±7.7 vs ctrl, 100 ±9.2, p<0.05) in 8-week-old female mice. In contrast, ovariectomy (reduced circulating E2 levels) up regulated the Adgrl1 expression (OVX, 156.9 ±12.6 vs ctrl, 100 ±19.1, p<0.05). The RNA in situ hybridization demonstrated that Adgrl1 is co-localized with about 46 ±9% estrogen receptor 1 (α) expression in the VMH. Discussion and conclusion: Our findings suggest that age, estrogen levels, and sex affect Adgrl1 expression. In conclusion, changes in Adgrl1 expression may explain sex and age differences in the pathogenesis of metabolic disorders such as type 2 diabetes and obesity, and their differential responses to a given treatment. Presentation: Saturday, July 12, 2025