The overall aim of the present PhD project was to investigate the impact of skeletal muscle interleukin 6 (IL-6) on adipose tissue and liver metabolism during exercise and fasting and to examine the influence of training state on fasting-induced metabolic regulation in human adipose tissue. The following hypotheses were tested: 1) skeletal muscle IL-6 is required for regulation of key factors in glucose production and regulation of substrate utilization in the liver during prolonged exercise in mice. 2) skeletal muscle IL-6 is required for the regulation of substrate production in the liver and adipose tissue during fasting in mice. 3) fasting induces molecular regulation of lipolysis and glyceroneogenesis in human adipose tissue and training state influences fasting-induced metabolic regulation in human adipose tissue. 4) skeletal muscle IL-6 is required for regulation of lipolysis and glyceroneogenesis in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) during exercise in mice.
Study I demonstrated that prolonged exercise increased hepatic STAT3 phosphorylation and hepatic PEPCK protein in both muscle-specific IL-6 knockout (IL-6 MKO) and control mice suggesting that hepatic IL-6 signaling and gluconeogenic capacity increased with prolonged exercise independent of skeletal muscle IL-6.
Study II demonstrated that fasting increased hepatic PEPCK protein and PDH phosphorylation as well as increased HSL, ATGL, perilipin and PDH phosphorylation in SAT in both IL-6 MKO and control mice. This suggests that skeletal muscle IL-6 is not necessary for fasting-induced increase in hepatic gluconeogenic capacity and regulation of substrate utilization or fasting-induced regulation of lipolytic enzymes and the availability of pyruvate for glyceroneogenesis in SAT.
Study III demonstrated that trained subjects had higher OXPHOS protein in the fed state and higher ATGL, HSL and PDH phosphorylation during fasting in SAT than untrained subjects. This indicates that training state influences basal oxidative capacity as well as the capacity for regulation of lipolysis and pyruvate availability for glyceroneogenesis during fasting in human SAT.
Study IV demonstrated that a single exercise bout increased HSL phosphorylation in VAT and decreased PEPCK protein in SAT in both inducible muscle-specific IL-6 knockout (IL-6 iMKO) and control mice. This suggests that exercise regulates lipolytic enzymes as well as glyceroneogenic capacity in an adipose tissue depot-specific manner and that this was independent of skeletal muscle IL-6. Furthermore, lack of skeletal muscle IL-6 appeared to enhance PDH phosphorylation during exercise in VAT suggesting that skeletal muscle IL-6 influences pyruvate availability for glyceroneogenesis during exercise in an adipose tissue depot-specific way.
Taken together, these present studies indicates that skeletal muscle IL-6 has minor effects in liver, SAT and VAT during exercise and fasting, but influences adipose tissue and liver metabolic regulation in the basal state.