Inhibition of endocannabinoid synthesis enzymes DAGL and NAPE-PLD transiently lowers body weight and alters glucose homeostasis during a high-fat diet challenge in mice

Abstract Background Cannabinoid receptor 1 inhibition poses an effective treatment strategy in obesity, but has a risk of psychiatric side effects. As high-fat diet (HFD)-feeding acutely increases expression of endocannabinoid synthesis enzymes and circulating endocannabinoid levels in mice, here we tested whether inhibition of these enzymes alleviates metabolic disturbances caused by high-fat diet feeding. Methods C57BL/6J mice received daily intraperitoneal injections with a NAPE-PLD inhibitor (LEI-401), DAGL inhibitor (DH-376), or vehicle for 1 week while on a HFD. An extra group of vehicle-treated mice was maintained on regular chow diet. Results Both inhibitors effectively lowered blood and brain levels of endocannabinoids after 1 week of treatment. DH-376 reduced plasma insulin levels compared with vehicle (−53%) already within 2 h after the first dose. In contrast, LEI-401 did not change insulin or glucose levels. Both inhibitors suppressed caloric intake during the first day of treatment (−25% and −21%, respectively). In addition, LEI-401 elevated carbohydrate oxidation. The combined effect was a 2.0 and 1.6 g lower body weight after 24 h, respectively. Nevertheless, after 1 week body weight was no longer different between the HFD-fed groups. Moreover, DH-376 increased brown adipose tissue weight and reduced insulin-stimulated glucose uptake. Conclusions DAGL and NAPE-PLD inhibition effectively lower levels of endocannabinoids and related bioactive lipids. Both inhibitors caused a transient reduction in food intake and body weight, but also led to alterations in glucose homeostasis. The long-term effects of endocannabinoid biosynthesis inhibitors on (cardio)metabolic health remains to be investigated.