Champagne CD, Houser DS, Fowler MA, Costa DP, Crocker DE. Gluconeogenesis is associated with high rates of tricarboxylic acid and pyruvate cycling in fasting northern elephant seals. Am J Physiol Regul Integr Comp Physiol 303: R340 -R352, 2012. First published June 6, 2012 doi:10.1152/ajpregu.00042.2012.-Animals that endure prolonged periods of food deprivation preserve vital organ function by sparing protein from catabolism. Much of this protein sparing is achieved by reducing metabolic rate and suppressing gluconeogenesis while fasting. Northern elephant seals (Mirounga angustirostris) endure prolonged fasts of up to 3 mo at multiple life stages. During these fasts, elephant seals maintain high levels of activity and energy expenditure associated with breeding, reproduction, lactation, and development while maintaining rates of glucose production typical of a postabsorptive mammal. Therefore, we investigated how fasting elephant seals meet the requirements of glucosedependent tissues while suppressing protein catabolism by measuring the contribution of glycogenolysis, glycerol, and phosphoenolpyruvate (PEP) to endogenous glucose production (EGP) during their natural 2-mo postweaning fast. Additionally, pathway flux rates associated with the tricarboxylic acid (TCA) cycle were measured specifically, flux through phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate cycling. The rate of glucose production decreased during the fast (F 1,13 ϭ 5.7, P ϭ 0.04) but remained similar to that of postabsorptive mammals. The fractional contributions of glycogen, glycerol, and PEP did not change with fasting; PEP was the primary gluconeogenic precursor and accounted for ϳ95% of EGP. This large contribution of PEP to glucose production occurred without substantial protein loss. Fluxes through the TCA cycle, PEPCK, and pyruvate cycling were higher than reported in other species and were the most energetically costly component of hepatic carbohydrate metabolism. The active pyruvate recycling fluxes detected in elephant seals may serve to rectify gluconeogeneic PEP production during restricted anaplerotic inflow in these fasting-adapted animals. pinnipedia; nuclear magnetic resononace; glucose production NEARLY ALL ANIMALS experience periods of food deprivation, frequently as a result of seasonal variation in food availability or the requirements of reproduction. Animals usually respond to fasting by reducing their overall metabolic rate, increasing their reliance on lipid reserves to meet energetic costs, and conserving lean tissue to preserve vital organ function (11). Select tissues, however, cannot use lipid as an energy source, and some protein must be degraded to supply the precursors for gluconeogenesis to meet the energy needs of these tissuesincluding the brain, red blood cells, and renal medulla. The commitment of amino acids to gluconeogenic pathways depletes protein reserves, compromising vital organ function in fasting animals (24). Terminal starvation occurs once lipid reserves are depleted or the loss of prote...