Molekulare Mechanismen der metabolischen Anpassung an körperliche Aktivität: Akute Antwort der Leber und die Rolle von Interleukin-6

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

Lipidomics Analysis Reveals Efficient Storage of Hepatic Triacylglycerides Enriched in Unsaturated Fatty Acids after One Bout of Exercise in Mice

Background: Endurance exercise induces lipolysis, increases circulating concentrations of free fatty acids (FFA) and the uptake and oxidation of fatty acids in the working muscle. Less is known about the regulation of lipid metabolism in the liver during and post-exercise

Medium Chain Acylcarnitines Dominate the Metabolite Pattern in Humans under Moderate Intensity Exercise and Support Lipid Oxidation

Background: Exercise is an extreme physiological challenge for skeletal muscle energy metabolism and has notable health benefits. We aimed to identify and characterize metabolites, which are components of the regulatory network mediating the beneficial metabolic adaptation to exercise

Hepatokines - a novel group of exercise factors

Regular physical activity not only improves the exercise capacity of the skeletal muscle performing the contractions, butit is beneficial for the whole body. An extensive search for exercise factors mediating these beneficial effects has been going on for decades. Particularly skeletal muscle tissue has been investigated as a source of circulating exercise factors, and several myokines have been identified. However, exercise also has an impact on other tissues. The liver is interposed between energy storing and energy utilising tissues and is highly active during exercise, maintaining energy homeostasis. Recently, a novel group of exercise factorstermed hepatokineshas emerged. These proteins (fibroblast growth factor 21, follistatin, angiopoietin-like protein 4, heat shock protein 72, insulin-like growth factor binding protein 1) are released from the liver and increased in the bloodstream during or in the recovery after an exercise bout. In this narrative review, we evaluate this new group of exercise factors focusing on the regulation and potential function in exercise metabolism and adaptations. These hepatokines may convey some of the beneficial whole-body effects of exercise that could ameliorate metabolic diseases, such as obesity or type 2 diabetes

Signals from the Circle: Tricarboxylic Acid Cycle Intermediates as Myometabokines

Regular physical activity is an effective strategy to prevent and ameliorate aging-associated diseases. In particular, training increases muscle performance and improves whole-body metabolism. Since exercise affects the whole organism, it has countless health benefits. The systemic effects of exercise can, in part, be explained by communication between the contracting skeletal muscle and other organs and cell types. While small proteins and peptides known as myokines are the most prominent candidates to mediate this tissue cross-talk, recent investigations have paid increasing attention to metabolites. The purpose of this review is to highlight the potential role of tricarboxylic acid (TCA) metabolites as humoral mediators of exercise adaptation processes. We focus on TCA metabolites that are released from human skeletal muscle in response to exercise and provide an overview of their potential auto-, para- or endocrine health-promoting effects