An important consideration for the development of therapeutic LepR agonists is that the serum levels of endogenous leptin are highly elevated in the context of human obesity, ranging from 5 ng/ml (0.3 nM) in lean individuals to as high as 100 ng/ml (6 nM) in obesity33,34. Here, LEPR is linked to obesity due to melanocortin 4 receptor deficiency.