INS and obesity due to melanocortin 4 receptor deficiency: Potential explanations for the differences between mice with hypothalamic obesity and diet-induced obesity may be that (a) neural inputs to liver — or adipose, which could secondarily affect liver — caused a subset of FoxOs to be inactivated, leading to decreased expression of Apom and potentially other FoxO targets, or that (b) the lipid content of the lard-rich obesogenic diet may have caused independent effects on S1P metabolism that overrode any effects of hepatic insulin signaling.