Several factors may contribute to this phenomenon, including saturation of blood brain barrier transporters of leptin, saturation and downregulation of its receptors in kisspeptin-expressing neurons, obesity-induced endoplasmic reticulum stress in target neurons, and a negative feedback loop engrained within its own signaling cascade, which activates in the face of leptin overactivity [124]. Here, LEP is linked to obesity due to melanocortin 4 receptor deficiency.