In obesity, where excessive amounts of leptin are produced by adipocytes, the hypothalamic–pituitary axis becomes resistant to leptin signaling, presumably by over-activating negative feedback regulators, including the suppressor of cytokine signaling 3 (SOCS3), protein tyrosine phosphatase 1B (PTP1B), and T cell protein tyrosine phosphatase (TCPTP). This evidence concerns the gene SOCS3 and obesity due to melanocortin 4 receptor deficiency.