Combined, we propose that fatty liver-associated whole body glucose intolerance and insulin resistance are connected to dysregulated liver lipolysis due to changes in PLIN5 abundance and insufficient PNPLA3, likely leading to poorly controlled fatty acid metabolic fluxes that spill over to bioactive lipid synthesis that influence hepatic insulin action (57, 58), and downstream signaling (53, 54). This evidence concerns the gene PNPLA3 and Insulin resistance.