N-Oleoylglycine-Induced Hyperphagia Is Associated with the Activation of Agouti-Related Protein (AgRP) Neuron by Cannabinoid Receptor Type 1 (CB1R).

N-Acyl amino acids (NAAAs) are conjugate products of fatty acids and amino acids, which are available in animal-derived food. We compared the effects of N-arachidonoylglycine (NAGly), N-arachidonoylserine (NASer), and N-oleoylglycine (OLGly) on in vivo food intake and in vitro [Ca2+]i of Agouti-related protein (AgRP) neurons to identify the role of these compounds in energy homeostasis. Hypothalamic neuropeptide expression and anxiety behavior in response to OLGly were also tested. To further identify the underlying mechanism of OLGly on food intake, we first detected the expression level of potential OLGly receptors. The cannabinoid receptor type 1 (CB1R) antagonist was cotreated with OLGly to analyze the activation of AgRP neuron, including [Ca2+]i, expression levels of PKA, CREB, and c-Fos, and neuropeptide secretion. Results demonstrated that only OLGly (intrapertioneal injection of 6 mg/kg) can induce hyperphagia without changing the expression of hypothalamic neuropeptides and anxiety-like behavior. Moreover, 20 μM OLGly robustly enhances [Ca2+]i, c-Fos protein expression in AgRP neuron, and AgRP content in the culture medium. OLGly-induced activation of AgRP neuron was completely abolished by the CB1R-specific antagonist, AM251. In summary, this study is the first to demonstrate the association of OLGly-induced hyperphagia with activation of the AgRP neuron by CB1R. These findings open avenues for investigation and application of OLGly to modulate energy homeostasis.