Introduction: GLP-1 receptor agonists are the number one drug prescribed for the treatment of obesity and type 2 diabetes. These drugs are not, however, without side effects, and in an effort to maximize therapeutic effect while minimizing adverse effects, gut hormone co-agonists received considerable attention as new drug targets in the fight against obesity. Numerous previous reports identified the neuropeptide oxytocin (OXT) as a promising anti-obesity drug. The aims of this study were to evaluate OXT as a possible co-agonist for GLP-1 and examine the effects of its co-administration on food intake (FI) and body weight (BW) in mice. Methods: FI and c-Fos levels were measured in the feeding centers of the brain in response to an intraperitoneal injection of saline, OXT, GLP-1, or OXT/GLP-1. The action potential frequency and cytosolic Ca2+ ([Ca2+]i) in response to OXT, GLP-1, or OXT/GLP-1 were measured in ex vivo paraventricular nucleus (PVN) neuronal cultures. Finally, FI and BW changes were compared in diet-induced obese mice treated with saline, OXT, GLP-1, or OXT/GLP-1 for 13 days. Results: Single injection of OXT/GLP-1 additively decreased FI and increased c-Fos expression specifically in the PVN and supraoptic nucleus. Seventy percent of GLP-1 receptor-positive neurons in the PVN also expressed OXT receptors, and OXT/GLP-1 co-administration dramatically increased firing and [Ca2+]i in the PVN OXT neurons. The chronic OXT/GLP-1 co-administration decreased BW without changing FI. Conclusion: Chronic OXT/GLP-1 co-administration decreases BW, possibly via the activation of PVN OXT neurons. OXT might be a promising candidate as an incretin co-agonist in obesity treatment.

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