FIGURE 1.

¹³C labeling patterns in TAGs and glucose produced in liver after oral [U-¹³C₃]glycerol. a, [U-¹³C₃]glycerol may be used immediately as backbones for fatty acid esterification or in gluconeogenesis after phosphorylation (“direct” contribution). A fraction of [U-¹³C₃]glycerol may be further converted to other trioses and [U-¹³C₃]pyruvate entering the TCA cycle prior to glyceroneogenesis or gluconeogenesis (“indirect” contribution). The TCA cycle scrambles ¹³C extensively, labeling all the cycle intermediates, including oxaloacetate, that may exit the cycle producing double- or triple-labeled trioses. These trioses may be either glyceroneogenic or gluconeogenic. Because PEP is a common intermediate for DHAP (becoming glucose carbons 1–3) and GA3P (becoming glucose carbons 4–6), an equivalent ¹³C-labeling pattern is expected between glucose carbons 1–3 and carbons 4–6. Thus, the ratio [1,2-¹³C₂]/[2,3-¹³C₂] in glucose must be equal to the ratio [5,6-¹³C₂]/[4,5-¹³C₂] in glucose. b, however, PPP activity increases the ratio of [1,2-¹³C₂]/[2,3-¹³C₂], but not [5,6-¹³C₂]/[4,5-¹³C₂], by producing [1,2-¹³C₂]hexose. Gluconeogenesis directly from [U-¹³C₃]glycerol produces [1,2,3-¹³C₃]- or [4,5,6-¹³C₃]hexose. The entry of [1,2,3-¹³C₃]glucose 6-phosphate to PPP produces mainly [1,2-¹³C₂]fructose 6-phosphate through decarboxylation in the oxidative PPP followed by carbon rearrangement in the non-oxidative PPP. In contrast, ¹³C 3-unit (¹³C-¹³C-¹³C) in [4,5,6-¹³C₃]hexose remains the same even after passing through the PPP. Consequently, the ¹³C-labeling pattern in glucose carbons 1–3 is sensitive to PPP activity, but the pattern in glucose carbons 4–6 is not. Open circles, ¹²C; black circles, ¹³C; green circles, ¹³C after metabolism through the TCA cycle; red circles, ¹³C after metabolism through the PPP. F6P, fructose 6-phosphate; G3P, glycerol 3-phosphate; G6P, glucose 6-phosphate; GK, glycerol kinase; PEPCK, PEP carboxykinase; TPI, triose phosphate isomerase.