Leptin receptor agonist, E1/Aca, increases hypercapnic ventilatory response in the leptin-deficient ob/ob mice

Background: Obesity leads to sleep-disordered breathing (SDB), including obesity hypoventilation syndrome (OHS), which is characterized by daytime hypercapnia and hypoventilation during sleep. Current management of SDB is largely non-pharmacological, focusing on lifestyle modifications and continuous positive airway pressure (CPAP) therapy. While beneficial, these approaches have low adherence limiting their long-term effectiveness. Leptin, a hormone with known respiratory stimulatory effects, has shown potential as a pharmacological treatment for OHS, yet leptin resistance poses a significant barrier to its therapeutic use. A novel LEPRb agonist, E1/Aca, overcomes this limitation by crossing the blood-brain barrier (BBB) and bypassing leptin resistance mechanisms. Objective: This study investigates leptin and its analog E1/Aca as potential therapeutic agents to treat OHS. Methods: Male leptin-deficient (ob/ob) mice (n = 12) received vehicle, 1 mg/kg of leptin (positive control), or the same dose of E1/Aca intraperitoneally (IP) twice a day for 3 days in a crossover design, with a one-week washout period. Food intake and body weight were measured daily. Respiratory recordings were assessed using a modified plethysmography setup, focusing on the baseline breathing and the hypercapnic ventilatory response (HCVR). Results: As expected, leptin treatment induced weight loss and reduced food intake. Mice treated with E1/Aca also showed initial weight loss in the first days but then regained weight. Both E1/Aca and leptin reduced cumulative food intake. Chronic treatment with leptin or E1/Aca did not affect baseline breathing. However, E1/Aca and leptin significantly enhanced the HCVR, increasing ventilation and tidal volume in 8% CO 2 compared to the vehicle. Conclusions: E1/Aca increased the HCVR in leptin-deficient ob/ob mice and represents a promising therapeutic candidate for OHS. Grant support: R01 HL128970, R41 DA056239, R41 HL167326, 24CDA1270910 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.