Hepatic fuel metabolism during muscular work: role and regulation.

The increased fuel demands of the working muscle necessitate that metabolic processes within the liver be accelerated accordingly. The sum of changes in hepatic glycogenolysis and gluconeogenesis are closely coupled to the increase in glucose uptake by the working muscle, due to the actions of the pancreatic hormones. The exercise-induced rise in glucagon and fall in insulin interact to stimulate hepatic glycogenolysis, whereas the increase in gluconeogenesis is determined primarily by glucagon action. The increment in gluconeogenesis is caused by increases in hepatic gluconeogenic precursor delivery and fractional extraction as well as in the efficiency of intrahepatic conversion to glucose. Glucagon stimulates the latter two processes. Epinephrine may become important in the regulation of hepatic glucose production during prolonged or heavy exercise when its levels are particularly high. On the other hand, there is no evidence that hepatic innervation is essential for the rise in hepatic glucose production during exercise. Nonesterified fatty acid (NEFA) delivery to, uptake of, and oxidation by the liver are accelerated during prolonged exercise, resulting in an increase in ketogenesis. The rate of the first two of these processes is largely determined by factors that stimulate fat mobilization. The third step is regulated by both NEFA delivery to and glucagon-stimulated fat oxidation within the liver. The increase in hepatic fat oxidation produces energy that fuels gluconeogenesis. The shuttling of amino acids to the liver provides carbon-based compounds that are used for gluconeogenesis, transfers nitrogen to the liver, and supplies substrate for protein synthesis. During exercise, metabolic events within the liver, which are regulated by hormone levels and substrate supply, integrate pathways of carbohydrate, fat, and amino acid metabolism. These processes function to provide substrates for muscular energy metabolism and conserve carbon in glucose and nitrogen in protein.