OR12-06 Hypothalamic Adgrl1 Is A Potential Glucoreceptor Involved In Regulating Energy Balance, Glucose Homeostasis, And Leptin Sensitivity In Mice

Disclosure: D.J. Samuel: None. T.S. Faniyan: None. M.U. Raza: None. S. Bathina: None. K.H. Chhabra: None. The hypothalamus regulates energy and glucose homeostasis by influencing glucose-stimulated insulin secretion, insulin sensitivity, and activating the hypoglycemia counterregulatory response. Although hypothalamic glucose transporters coupled with glucose metabolism are involved in mediating some of these effects, it is unknown whether a plasma membrane receptor that directly binds to glucose can contribute to hypothalamic glucose signaling. We used affinity chromatography and biotin-labeled glucose to enrich glucose-binding plasma membrane proteins/receptors in the mouse hypothalamus and then performed proteomic analyses. Adhesion G-protein Coupled Receptor L1 (Adgrl1) was a top candidate as a potential glucoreceptor. Therefore, we generated Adgrl1(loxp/loxp) mice to knockout Adgrl1 in the ventromedial hypothalamus (VMH; a region known for glucose sensing) using the Cre-Lox system to determine the role of Adgrl1(VMH) in glucose homeostasis, energy balance, and leptin sensitivity. We measured body weight, food intake, 6h fasting blood glucose and plasma insulin levels. We also determined leptin sensitivity in the Adgrl1(VMH) deficient mice. We observed that 24 weeks old male Adgrl1(VMH) deficient mice had higher (p<0.05) body weight (49 ±3.6 vs 35 ±1.3 g), blood glucose (210 ±4 vs 180 ±5 mg/dl), plasma insulin levels (2.92 ±0.24 vs 1.63 ±0.09 ng/ml), and leptin levels (21.11 ±1.72 vs 8.38 ±0.80 ng/ml) compared to their control littermates. Hyperinsulinemia and hyperleptinemia persisted in the Adgrl1(VMH) knockout mice even when they were weight-matched to their littermate controls, indicating the direct role of Adgrl1(VMH) in regulating plasma insulin and leptin levels. Ovariectomy in female mice was necessary to unmask the effects of Adgrl1(VMH) deficiency on energy and glucose homeostasis. To assess acute leptin sensitivity, we injected Adgrl1(VMH) deficient mice and their littermate control mice with recombinant mouse leptin (5 mg/Kg, i.p., twice a day for two days), and monitored their body weight and food intake. Male Adgrl1(VMH) deficient mice were more susceptible (p<0.05) to leptin mediated decrease in food intake (-1 ±0.1 vs -0.5 ±0.005, g/day; these values are relative to each group’s corresponding baseline food intake) than their littermate controls. Decrease in body weight was similar in both groups with this acute leptin treatment. These findings suggest that Adgrl1(VMH) is essential in regulating energy and glucose homeostasis in a sex-specific manner. Moreover, Adgrl1(VMH) contributes to leptin’s acute effects on food intake. Therefore, hypothalamic Adgrl1 could be a target to enhance leptin sensitivity in future therapies for treating type 2 diabetes and obesity. Presentation: Friday, June 16, 2023