Item – Theses Canada

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Fediuc, Sergiu.
Skeletal muscle and whole-body regulation of substrate partitioning by nutritional and pharmacological AMPK activation.
Ph. D. -- York University, 2009
Ottawa : Library and Archives Canada = Bibliothèque et Archives Canada, [2010]
3 microfiches
Includes bibliographical references.
The first three studies outlined in this thesis were intended to enhance our knowledge about the effects of palmitate-, troglitazone-, and AICAR-induced AMPK activation on various aspects of glucose and fatty acid (FA) metabolism in skeletal muscle. Our results provide novel evidence that FAs autoregulate their metabolic fate in skeletal muscle cells by directly promoting the phosphorylation and activation of AMPK and ACC in a dose dependant manner. From these data we hypothesized that by upregulating the AMPK/ACC signaling cascade, high circulating FA levels saturate the ability of this pathway to respond to exogenous AMPK agonists. To overcome this, thiazolidinediones (TZDs) are a class of drugs that reduce circulating FA levels by promoting expression of lipid storage genes in adipose tissue. In addition, they have also been demonstrated to activate the AMPK system. Treatment of L6 cells with the TZD troglitazone reduces FA uptake and increases FA oxidation, effects that are partially mediated by AMPK activation. Additionally, troglitazone also promotes an increase in insulin stimulated glucose uptake, and shifts glucose metabolism away from glycogen synthesis and towards an increase in lactate production. Since skeletal muscle glycogen synthesis is an important process that accounts for the majority of glucose disposal in the body, we wanted to test whether the results obtained in skeletal muscle cells are representative of intact isolated muscles. Indeed, this seems to be the case, as soleus muscles (oxidative) treated with AICAR exhibited a similar shift in glucose metabolism away from glycogen synthesis in favour of increased lactate production. This effect, however, appears to be fiber type specific as isolated epitrochlearis muscles (glycolytic) do not experience this metabolic shift. The final study was intended to provide an integrated look at the effects of 2-week AICAR injections on whole-body glucose and FA homeostasis in the rat. The results of this investigation confirm that this drug shifts whole-body glucose metabolism in favour of lactate production. We also demonstrate that in week 1 FA utilization is upregulated even though whole-body energy expenditure is reduced by AICAR. In week 2, treated animals adapted to the drug, as any initial disturbances in substrate utilization observed in week 1 returned to normal with the exception of spontaneous physical activity which was increased. Collectively, these effects led to a reduction in whole-body adiposity at the end of the study.