Even though the increase of adipose tissue mass in obesity increases production of leptin, soluble leptin receptors (LEPRs, the main leptin binding proteins in circulation that result from LEPR cleavage and regulate leptin function and bioavailability) decrease, while leptin transport into the central nervous system (CNS) is not commensurately increased, resulting in decreased hypothalamic leptin signaling, increased leptin levels and leptin resistance [47,48,49,50]. This evidence concerns the gene LEP and obesity due to melanocortin 4 receptor deficiency.