SAT-549 - Adgrl1 Is A Brain Glucose Sensor Integrating Peripheral Hormonal Signals to Regulate Systemic Glucose Homeostasis

Adhesion G-protein coupled receptor L1 (Adgrl1) is a glucose receptor highly expressed in the hypothalamic ventromedial nucleus (VMH) and involved in energy balance regulation. Loss of Adgrl1 leads to obesity and type 2 diabetes-like phenotypes in both mice and humans, conditions commonly associated with leptin and insulin resistance. The role of Adgrl1 in brain glucose sensing and neurohormonal regulation remains largely unknown. Therefore, in this study, we investigated the potential interaction of glucose, insulin and leptin signaling with Adgrl1-expressing (Adgrl1VMH) neurons in the VMH. First, we measured hypothalamic Adgrl1 expression by qPCR in male C57BL/6J mice across different ages and following leptin or insulin treatments. Using in vivo wireless fiber photometry, we assessed Adgrl1VMH neuronal activity in freely moving mice, following intraperitoneal administration of glucose, insulin, or leptin. We injected Cre-inducible AAVs encoding fluorescence calcium indicator (GCaMP6s) into the VMH of 6-8 wk old male Adgrl1-Cre mice. Three wk later, we recorded real time calcium dynamics as a proxy for the neuronal activity. Finally, we also selectively activated Adgrl1VMH neurons using chemogenetics and assessed their energy expenditure profile, insulin sensitivity and glucose tolerance. We observed that hypothalamic Adgrl1 expression significantly decreased (8 wk, 100±6.53 vs 24 wk, 30.7±2.6 %, p<.05) with aging. Leptin reduced hypothalamic Adgrl1 expression in both young adult (8 wk: Con, 100 ±4.3 vs Lep, 62.9 ±3.9 %, p<.05) and mature adult (24 wk: Con 100 ±7.3 vs Lep 72 ±7.9%, p<.05) mice, whereas insulin increased (Con, 100 ±7.2 vs Ins, 171.7 ±10.2 %, p<.05), the Adgrl1 gene expression. Glucose administration within a few minutes markedly decreased (AUC ∆F/F x sec: Baseline, 61,476 ±3,287 vs Glu, 33,975 ±2,560, p<.05) Adgrl1VMH neuronal activity, suggesting a direct role in glucose sensing. In contrast, we did not observe any changes in Adgrl1VMH neuronal activity with insulin treatment. Interestingly, the activation of Adgrl1VMH neurons improved insulin sensitivity (AUC-glucose: 17,990 ±665.4 vs 15,307 ±408.8 mg/dl, p< 0.05) and glucose tolerance without affecting energy expenditure, which indicates that Adgrl1 specifically targets peripheral glucose disposal. In addition, leptin also reduced Adgrl1VMH neuronal activity (AUC ∆F/F: Baseline, 55,412 ±1,592 vs Glu, 39,255 ±393.3, p<.05), supporting Adgrl1’s role as a negative regulator of leptin signaling. Collectively, these findings suggest that Adgrl1 is a novel centrally acting glucose sensor that integrates peripheral hormonal signals and is indispensable for maintaining systemic glucose homeostasis. Therefore, Adgrl1 could be a highly specific therapeutic target for treating metabolic disorders and age-related insulin resistance without impacting overall caloric balance.

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