Enhanced 2-arachidonoyl glycerol-dependent CB1 activation contributes to feeding dysregulation in KK-A ^y mice

The endocannabinoid (EC) system in the central and peripheral nerves plays a crucial role in various physiological processes, including feeding behaviour and energy metabolism. In particular, gut ECs stimulate appetite, and excessive activation of the system can induce hedonic eating, leading to obesity. Previous studies have indicated elevation of gut EC levels in high-fat diet-induced or genetically obese rodents. The present study aimed to expand our understanding of gut ECs involved in feeding behaviour during obesity by characterising the profiles of arachidonic metabolites, including ECs, in the gut and by examining their impact on feeding behaviour in KK-A ^y mice, an obesity model established by crossing diabetic KK mice with lethal yellow (A ^y ) mice. KK-A ^y mice exhibit hyperphagia compared with lean mice under either free-feeding condition or refeeding condition after 24 h of food deprivation. Meal pattern analyses revealed that hyperphagia in KK-A ^y mice was primarily due to higher meal frequency rather than meal size or interval, suggesting a defect in hunger control. In addition, levels of EC and other arachidonic acid metabolites such as prostaglandin E₂ and F_2α were elevated in KK-A ^y mice. Pharmacological blockade of the peripheral cannabinoid receptor 1 (CB1) and diacylglycerol lipase, but not N-acyl phosphatidylethanolamine phospholipase D, reduced food intake, as did treatment with cyclo-oxygenase-2 inhibitors. These findings suggest that intestinal 2-arachidonoyl glycerol-dependent CB1 activation contributes to hyperphagic behaviour in KK-A ^y mice and PGs are involved in feeding control.