OR31-01 Hypothalamic glucose receptor - ADGRL1 - regulates leptin function in mice

Abstract D.J. Samuel, DO: None. T.S. Faniyan: None. K.H. Chhabra: None. We recently identified Adgrl1 as a glucose receptor in the hypothalamus. Adgrl1 knockout mice exhibit insulin resistance and obesity followed by fasting hyperglycemia. Because Adgrl1 is involved in energy and glucose homeostasis, here we determined its role in mediating leptin function. Leptin is a hormone involved in controlling energy balance. To investigate the influence of Adgrl1 in modulating leptin function, we measured the effects of leptin on food intake and bodyweight in mice that lacked Adgrl1 specifically in the ventromedial nucleus of the hypothalamus (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. We injected AAV2-hSyn-DIO-mCherry (control group) and AAV2-hSyn-DIO-hM3D (Gq)-mCherry (experimental group) viral vectors into the VMH of 6-8 weeks old Adgrl1Cre mice. Following a three-week recovery period post-surgery, we administered clozapine N-oxide (CNO, 1 mg/Kg, i.p. for determining acute effects; 120 µg/day infusion using osmotic minipumps for studying chronic effects) to activate Adgrl1VMH neurons. We also measured Adgrl1 gene expression in the hypothalamus using qRT-PCR in high-fat diet fed or leptin deficient 24 weeks old male mice. Finally, we quantified the Adgrl1 expression in 8-10 weeks old WT C57Bl/6 mice injected with leptin (5 mg/Kg, i.p.) or saline as a control. Unexpectedly, we observed that Adgrl1VMH deficient mice had reduced food intake (Exp, -1 ±0.1 vs Con, -0.5 ±0.005, g/day, p<0.05) in response to exogenous leptin despite obesity and hyperleptinemia. In contrast, chronic activation of the Adgrl1VMH neurons induced leptin resistance (Δ food intake/day: Con, -1.9 ±0.02 vs Exp, 0.3 ±0.05; Δ body weight after 48h: -2 ±0.1 vs -0.5 ±0.1 g p<0.05) even in the absence of obesity. The activation of Adgrl1VMH neurons increased baseline blood glucose levels (Con, 222 ±17 vs Exp, 338 ±23 mg/dl, p<0.05) and improved insulin sensitivity (AUC-glucose: 17,165.6 ±750 vs 15,225 ±1,130 mg/dl, p<0.05). These results indicate the differential effects of Adgrl1 on leptin sensitivity and glucose homeostasis. Furthermore, administration of leptin increased hypothalamic Adgrl1 expression (saline, 100 ±13.2 vs leptin, 193.8 ±36.2 % relative to control). Interestingly, leptin deficient ob/ob mice and leptin-resistant high-fat diet (HFD) fed mice also showed upregulation of hypothalamic Adgrl1 expression (ob/ob, 164 ±17 vs WT, 100 ±17.3 % relative to WT; HFD, 168 ±13 vs control, 100 ±18 % relative to control). Together, these findings identify a fundamental mechanism involving a crosstalk between hypothalamic ADGRL1 signaling and leptin function to influence energy balance. This information may be useful in establishing the molecular basis of leptin resistance in obesity. Sunday, June 2, 2024