Jakob Knudsen:
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Physical activity can lead to metabolic disease and treatment of several metabolic diseases include exercise training. Skeletal muscle has, due to its central role in glucose and fat metabolism at rest and during exercise been studied in detail with regard to exercise training. The role of both liver and adipose tissue regulation in whole body metabolism has come in to focus and it has been shown that both tissues are subject to exercise training-induced adaptations. However, the contribution of endocrine factors to the regulation of exercise training-induced adaptations in liver and adipose tissue metabolism is unknown. It has been suggested that myokines, such as IL-6, released from skeletal muscle affects liver and adipose tissue and are involved in the regulation of exercise training adaptations. Thus, the aim of this thesis was to investigate the role of skeletal muscle derived IL-6 in the regulation of liver and adipose tissue metabolism in mice.
The aim of study I was to investigate the role of IL-6 in the regulation of UCP1 expression in inguinal white adipose tissue (iWAT) in mice. The study demonstrated that IL-6 is required for the exercise training and cold exposure-induced increase in UCP1 mRNA and protein content in iWAT. In addition the study demonstrated that daily transient increases in IL-6 increases UCP1 mRNA content in iWAT. These findings indicate that IL-6 is required for basal, cold and exercise traininginduced iWAT UCP1 expression in mice.
The aim of study II was to investigate the effect of exercise on key factors in liver glucose and fat metabolism. This study demonstrated that PDH and ACC phosphorylation was decreased and that changes in hepatic PEPCK and G6Pase protein content does not contribute to gluconeogenesis during 1h of exercise in mice. These findings indicate that during 1h of exercise the liver utilizes carbohydrates for oxidation rather than gluconeogenesis and that gluconeogenic activity during 1h of exercise is not regulated through increases in protein content.
The aim of study III was to investigate the role of skeletal muscle derived IL-6 in the regulation of changes in key factors in WAT metabolism in response to HFD and HFD combined with exercise training. The study demonstrated that skeletal muscle derived IL-6 regulates iWAT but not eWAT metabolism. In addition, these finding showed that skeletal muscle derived IL-6 are important for the basal and HFD induced regulation of glucose metabolism, lipolysis and lipogenesis in iWAT, possibly through regulation of AMPK. Together these findings indicate that skeletal muscle derived IL-6 is important for basal iWAT metabolism both on chow and HFD, but only plays a minor role in exercise training-induced adaptations in iWAT metabolism while on HFD.
The aim of study IV was to investigate the role of skeletal muscle derived IL-6 in the regulation of changes in key factors in liver metabolism in response to HFD and HFD combined with exercise training. This study demonstrated that skeletal muscle derived IL-6 may indirectly regulate PEPCK protein content when on HFD and that skeletal muscle derived IL-6 may regulate skeletal muscle and hepatic fat metabolism. These findings indicate an indirect role of skeletal muscle derived IL-6 in the regulation of liver metabolism in response to HFD and HFD combined with exercise training.
In conclusion these findings demonstrate that IL-6 is an important regulator of fat metabolism and uncoupling in iWAT, but not in eWAT in mice and that skeletal muscle derived IL-6 may indirectly regulate liver metabolism in response to HFD. Furthermore these findings show that ATP production during exercise in the liver may derive from carbohydrate rather than fatty acid oxidation and that increases in gluconeogenic enzyme content does not contribute to hepatic glucose production during 1h of acute exercise in mice.