Influence of age and endurance training on hepatic gluconeogenesis in Fischer 344 rats.

摘要

I have focused my dissertation on determining the influence of age (non-diseased) on hepatic gluconeogenesis (the extraction of specific metabolites from the blood in order to generate new glucose) in Fischer 344 rats. The synthesis of glucose is of utmost importance as several tissues, such as brain and nervous tissue, erythrocytes and renal medulla utilize glucose as their primary, or sole, fuel source. Further, as regularly performed vigorous exercise in rats and humans has been shown to induce adaptations that slow or reverse many changes in structure and function associated with aging and disease, I investigated the capacity of chronic exercise training to attenuate age-related declines in gluconeogenesis. I examined these topics from a variety of approaches. I measured radioactive lactate uptake into glucose (gluconeogenesis) and glycogen (glyconeogenesis, the synthesis of glycogen from a substrate that enters the pathway below the level of the triose phosphates), and radioactive fructose uptake into glycogen (glycogenesis, the synthesis of glycogen from a substrate that enters the pathway at or above the level of the triose phosphates) in liver slices to determine the dynamics of glucose production and glycogen synthesis from these metabolic substrates. I administered a gluconeogenic-inhibiting drug, 3-mercaptopicolinic acid, to the rats in vivo and examined the effects on endurance performance to assess the contribution of gluconeogenesis with age and training. I have also studied the dose-response relationship between the sympathetic neurotransmitter norepinephrine and the stimulation of gluconeogenesis and glycogen synthesis in rat liver slices with age and training. I have assessed the contributions of three hormone-specific regulators of gluconeogenesis: glucagon, ;Throughout these investigations, I assessed hepatic metabolism and its regulation through whole animal experimentation, metabolite synthesis, and enzymatic analyses. These approaches led to a number of important findings: (1) The capacity for gluconeogenesis and glycogen synthesis declined with advancing age, and those declines can be partly attributed to declines in the activity of the rate-limiting enzymes PEPCK and glycogen synthase, respectively; (2) training was found to attenuate some of the decline in gluconeogenesis observed with age, but not glycogen synthesis; (3) the site(s) of the training adaptation(s) in the liver were not in PEPCK, glycogen synthase, or lactate dehydrogenase (LDH) activity; and further, training did not affect liver LDH isozyme patterns or PEPCK steady state levels of mRNA; (4) when compared to results from young and middle-aged rats, old rat livers were least responsive to norepinephrine, glucagon, phenylephrine (