Gregory Shobert

Exercise and metformin are effective independent interventions for chronic diseases such as type 2 diabetes, obesity, and cardiovascular disease. However, beneficial muscular and cardiovascular adaptations to exercise are diminished when combined with metformin. Notably, exercise stimulates liver gluconeogenesis to supply energy to working muscles in the form of glucose. In contrast, metformin inhibits gluconeogenesis. The hypothesis that liver gluconeogenesis is required for muscular adaptations to exercise was tested in mice with a liver-specific deletion (KO) of cytosolic phosphoenolpyruvate carboxykinase (a key regulator of gluconeogenesis) and wildtype (WT) littermates. WT and KO mice receiving a high-fat diet to induce obesity were assigned to sedentary (SED) and exercise-trained (EX) groups. Body weight, adiposity, and maximal running speed (MRS), a marker of cardiovascular and muscular fitness, were similar between groups prior to exercise training. The comparable MRS was unexpected given that KO mice had ~40% lower liver glycogen, which is another source of glucose for working muscles. Six weeks of exercise blunted the diet-induced increase in body weight and adiposity in both genotypes. WT- and KO-SED mice showed a decline in MRS following the additional six weeks of sedentary behavior, however, this decline was prevented in WT-EX mice. MRS was also decreased in KO-EX mice even though exercise training restored liver glycogen and increased muscle glycogen two-fold compared to WT-EX mice. Together, these data suggest that liver gluconeogenesis is necessary for exercised-induced adaptations in muscular performance and that an increase in liver and muscle glycogen is not sufficient to rescue the decreased performance.