Molecular mechanisms of the metabolic adaptation to physical exercise: Acute response of the liver and the role of interleukin-6

Abstract

Understanding the molecular mechanisms that determine the beneficial metabolic response to physical exercise may open up new therapeutic options to prevent and improve Type 2 Diabetes and related metabolic disorders. The focus of this thesis was on the liver as the main regulator of energy homeostasis and on interleukin-6 (IL-6) because it is released from the working muscle and could signal directly to the liver. A single bout of non-exhaustive endurance exercise caused a rapid and strong transcriptional response of several key regulators of glucose and fatty acid metabolism in the liver of mice that was more pronounced than in the working muscle at this early time point. The amount of insulin receptor substrate-2 protein was increased and insulin signalling, induced by glucose-stimulated endogenous insulin secretion, was amplified. Different stress-responsive pathways were transiently activated in the liver, most notably, mitogen-activated protein kinase (MAPK) signalling, as evidenced by the increased phosphorylation of c-Jun terminal kinase and an extracellular signal related kinase isoform and induction of MAPK target genes. IL-6-type cytokine signalling and p53 were also activated. Exercise-induced oxidative stress was not the stimulus for the hepatic stress response, because it could not be blocked by an antioxidant-enriched diet. It could, however, be linked directly or indirectly to the fall in plasma glucose, since the levels of hepatic gene expression correlated to glucose concentrations after the bout of exercise. Activation of AMPK and the depletion of hepatic glycogen confirmed that the exercising liver experienced acute energetic stress. IL-6-deficient (IL-6-/-) mice showed reduced endurance capacity, which might be caused by impaired activation of IL-6-dependent pathways resulting in reduced energy supply during exercise. However, plasma glucose, insulin and free fatty acid (FFA) levels and the decrease of hepatic glycogen were similar in exercised IL-6-/- and wildtype mice and the induction of gluconeogenic enzymes and other metabolic regulators studied was not impaired. The gluconeogenic response to fasting was also intact in IL-6-/- mice. Training-associated adaptations to regular physical activity, the improvement of glucose disposal and the relative increase in exercise endurance by four weeks of training, were also similar in the IL-6-/- mice. In contrast, IL-6-/- mice had a mild metabolic phenotype in the sedentary, fed state. The lack of IL-6 in the liver appeared to cause a weaker suppression of glucose production in response to insulin, leading to higher glucose and insulin and lower FFA levels. On the other hand, the IL-6-/- mice in our study had a persistently lower weight gain, accompanied by a slightly improved glucose tolerance. To conclude, the results from this thesis reveal that the liver responds intensely and acutely to physical exercise and that IL-6 is not essential for this acute metabolic response of the liver.

Ein besseres Verständnis der molekularen Mechanismen, welche die positive metabolische Anpassung an Sport vermitteln, kann dazu beitragen, neue therapeutische Optionen zur Prävention und Therapie von Typ-2-Diabetes zu entwickeln. Der Schwerpunkt der vorliegenden Arbeit waren die Leber als wichtigster Regulator der Energie-Homöostase sowie Interleukin-6, welches vom kontrahierenden Muskel produziert wird und als direktes Signal zur Leber fungieren könnte.