,26 Such an inverse association might be explained by the presence of a negative feedback loop among individuals with a prolonged state of obesity, whereby reductions in IGF binding protein 1 (IGFBP1) and IGF binding protein 2 (IGFBP2), as a result of obesity-associated hyperinsulinemia, may lead to increased negative feedback by free IGF1 (unbound to IGFBPs) on pituitary growth hormone secretion (a major regulator of IGF1 synthesis in the liver).27 This evidence concerns the gene IGF1 and obesity due to melanocortin 4 receptor deficiency.