IRS1 and obesity due to melanocortin 4 receptor deficiency: In obesity, hyperactivation of mTORC1 induced by excessive nutrition and mitogens can lead to phosphorylation of insulin receptor substrate 1 (IRS-1) by S6K1 [67,68,69] and negative regulation of insulin signaling by GRB10 (growth factor receptor bound protein 10) [70,71].