The finding in humans that leptin levels in cerebrospinal fluid are higher in obesity than in thin persons clearly demonstrates resistance at the receptor level.20,21 Mathematical modeling based on classic assumptions of receptor resistance suggests that at low to moderate levels of obesity, peripheral resistance dominates.18 The modeling also suggests that as obesity increases, resistance at both sites progressively worsens. The gene discussed is LEP; the disease is obesity due to melanocortin 4 receptor deficiency.