In addition to respiration, liver mitochondria possess high capacity anaplerotic and cataplerotic pathways that supply substrates for gluconeogenesis and other biosynthetic activities. Fluxes through these biosynthetic pathways are increased in insulin resistant liver and, hence, through the mitochondrial pathways that support them. The energetics associated with poorly controlled gluconeogenesis, for example, place a concomitant pressure on hepatic energy demand. During nonalcoholic fatty liver disease (NAFLD) this hepatic workload may impinge on compromised mitochondria, incite oxidative stress and inflammatory processes that reinforce insulin resistance. In this lecture, I will present in vivo stable isotope tracer data and explore how nutritional state, cell signaling and metabolic mechanisms regulate the anabolic workload of the liver. NAFLD results in the loss of normal metabolic responsiveness of hepatic oxidative flux, causing reduced flux in fed mice but elevated anaplerotic and oxidative flux in the fasted state. Conditional loss of hepatic insulin action also caused an upregulation of oxidative flux, while activation of mTORC1 recapitulated the effects of NAFLD by eliminating the normal metabolic flexibility of the TCA cycle. Preventing the upregulation of anaplerotic/cataplerotic and oxidative flux in obese mice prevented oxidative stress and inflammation in liver despite not reducing liver fat. Thus, metabolic flux through certain mitochondrial pathways in liver may contribute to the pathological effects of NAFLD.