In obesity and type 2 diabetes, these safeguards unravel the following: free fatty acids and inflammatory cues stimulate serine/threonine kinases that phosphorylate insulin-receptor substrate-1 (IRS-1) on inhibitory serine sites, disconnecting it from phosphatidyl-inositol-3-kinase (PI3K) and blocking downstream Akt activation; at the same time, gluconeogenic enzymes in the liver remain inappropriately active [75]. This evidence concerns the gene IRS1 and obesity due to melanocortin 4 receptor deficiency.