IRS1 and obesity due to melanocortin 4 receptor deficiency: The pro-inflammatory microenvironment induced by obesity then activates stress kinases and transcriptional programs—most notably c-Jun N-terminal kinase (JNK) and NF-κB—culminating in inhibitory serine phosphorylation of Insulin Receptor Substrate-1 (IRS-1) and impaired propagation of insulin-receptor signaling (89, 90).