LEP and obesity due to melanocortin 4 receptor deficiency: In 2001, Di Marzo et al. [57] were the first to relate leptin to the ECS, demonstrating that defective leptin signaling, observed in genetic models of obesity such as obese Zucker rats, and db/db and ob/ob mice, was associated with elevated hypothalamic endocannabinoids, especially 2-AG [57] (Table 1).