After prolonged fasting, blood glucose for consumption by the brain, the kidney medulla, and red blood cells is exclusively maintained by gluconeogenesis that primarily takes place in hepatocytes. The main precursors for hepatic gluconeogenesis are pyruvate, lactate, amino acids, and glycerol (derived from the backbone of triglycerides), which are converted to glucose via a series of reactions in the cytosol and mitochondria (Figure 2). After depletion of carbohydrate reserves, triacylglycerol stores are mobilized from adipose tissue, increasing FFAs and glycerol concentration in plasma. These fatty acids are taken up by the liver, where they can be stored or metabolized via β-oxidation to produce acetyl-CoA. In turn, acetyl-CoA can be further metabolized in mitochondria via the TCA cycle followed by OXPHOS or it can be converted to pyruvate. Glycerol, pyruvate, and ATP are then used in hepatic gluconeogenesis. The main portion of lactate is produced in a process known as the Cori cycle, in which lactate produced by glycolysis in exercising muscle is shuttled to the liver where it is converted back into glucose. Also in adipose tissue, glucose is metabolized
