MON-676 The glucose receptor Adgrl1 is a Novel Regulator of Leptin and Insulin Function

Abstract Disclosure: N. Hasan: None. D. Samuel: None. T. Faniyan: None. M. Hodges: None. N. Rashid: None. K.H. Chhabra: None. We recently identified adhesion G-Protein Coupled Receptor L 1 (Adgrl1) as a novel glucose receptor that is highly expressed in the ventromedial nucleus of the hypothalamus (VMH). Adgrl1 is necessary to regulate glucose and energy homeostasis. We demonstrated that mice lacking Adgrl1 develop insulin resistance and obesity, followed by fasting hyperglycemia. These findings were confirmed in humans in a recent study. Here, we investigated the role of hypothalamic Adgrl1 in mediating leptin and insulin function. We first measured the effects of leptin on food intake and body weight in mice lacking Adgrl1, specifically in VMH. Using in situ RNA hybridization, we then assessed the expression of Adgrl1 and leptin receptor (LepR) in the VMH. In addition, we selectively activated Adgrl1-expressing neurons in the VMH in Adgrl1Cre mice using chemogenetics involving designer receptors exclusively activated by designer drugs. Briefly, we injected viral vectors into the VMH of 6-8 weeks-old mice. Three weeks later, we administered clozapine N-oxide (CNO) to activate Adgrl1VMH neurons and measured insulin sensitivity and glucose tolerance. Finally, we measured the effects of exogenous leptin and insulin on hypothalamic Adgrl1 expression in different mouse models including high-fat diet (HFD)-fed and leptin-deficient (ob/ob) mice. Unexpectedly, we found that Adgrl1VMH deficient mice had reduced food intake (Exp, 2.9±0.2 vs Con, 4.2±0.5, g/day, p<0.05) in response to exogenous leptin despite obesity. We also observed that Adgrl1 co-expresses with the LepR in the VMH. In contrast, activation of the Adgrl1VMH neurons improved insulin sensitivity (AUC-glucose: 841.5±40.1 vs 781.5±26.1 mg/dl, p<0.05). These results indicate the differential effects of Adgrl1 on leptin sensitivity and glucose homeostasis. Furthermore, exogenous leptin administration decreased (Exp, 100±4.3 vs Con, 62.91±3.9 %, p<.0001) hypothalamic Adgrl1 expression in wild-type (WT) mice. Interestingly, hypothalamic Adgrl1 was elevated (Con, 100±7.8 vs HFD, 205.4±12.6 %, p<.0001) in high-fat diet-fed obese mice compared to normal chow-fed controls but decreased (Con, 100±2.2 vs Exp, 84.04±4.6 %, p<.05) with leptin administration. Conversely, leptin-deficient (ob/ob) mice exhibited lower hypothalamic Adgrl1 levels (Con, 100±9.7 vs ob/ob, 53.23±7.5 %, p<.01) compared to their WT counterparts. Moreover, exogenous insulin significantly increased hypothalamic Adgrl1 levels (Con, 100±5.0 vs Exp, 164.4±10.3 %, p<.0001), even in streptozotocin-induced diabetic mice. These findings reveal a novel role of hypothalamic Adgrl1 in mediating leptin and insulin actions in regulating glucose and energy metabolism. This information may be useful in establishing the molecular basis of leptin and insulin resistance in obesity and type 2 diabetes, and in developing strategies to treat these metabolic diseases. Presentation: Monday, July 14, 2025