INS and Insulin resistance: This simple model can explain the development of lipid-induced liver and muscle insulin resistance in obese rodents and humans (1, 4–10), as well as the mechanism by which weight loss (11), adiponectin (12), and liver-targeted mitochondrial uncouplers reverse insulin resistance in HFD-fed obese (13, 14) and lipodystrophic (15) insulin–resistant rodents.