INS and obesity due to melanocortin 4 receptor deficiency: It is important to note that AEA was previously described as a “gate opener” as diet-induced obesity in rodents enhanced liver AEA levels64,65 and its increase in the intestine was related to higher gut permeability, circulating endotoxemia, and inflammation.19 It has also been reported that high hepatic AEA levels inhibit hepatic insulin sensitivity, and cause hepatic TG accumulation and steatosis via cannabinoid CB1 receptor activation.64,65 Contrary to our studies, Bidu et al.66 and Kaliannan et al.67 reported an improvement of hepatic steatosis in homozygous fat-1+/+ mice.