IGFBP1 and obesity due to melanocortin 4 receptor deficiency: ,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