| Interleukin 6 (IL-6) is a pleiotropic cytokine involved with immune function, hematopoiesis, inflammation and oncogenesis. In contrast, AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that restores cellular energy levels in response to hypoxia and glucose deprivation. During exercise, IL-6 is released into the circulation, and AMPK is activated in multiple tissues. In this thesis, studies are reported that examine the possible role of IL-6 as a novel factor regulating AMPK activity during exercise. IL-6 knockout (KO) mice were studied to explore both this question and whether absence of IL-6 possibly contributed to the obesity, dyslipidemia and glucose intolerance that develops in these animals by 9 months of age.; Studies in incubated muscle demonstrate that IL-6 can activate AMPK and increase AMPK-mediated processes. We also found that this activation correlated temporally with a transient increase in the AMP:ATP ratio that returned to baseline as AMPK activity secondarily diminished. Interestingly, our data revealed that cyclic AMP, PKA activity and STAT3 were also increased during AMPK activation by IL-6 and treatment of the muscles with inhibitors of either event also inhibited IL-6-mediated AMPK activation.; Studies in 3-month-old IL-6 KO mice showed that they display reduced AMPK activity in muscle and adipose tissue. Exercise increased AMPK activity in these mice, however the absolute increase was less than in control animals. Finally, preliminary studies revealed that a decrease in cardiolipin content accompanied the decreased P-AMPK, suggesting mitochondrial dysfunction in the white muscle of IL-6 KO mice at age 3 months. Interestingly, at age 14 months, AMPK activity was increased in these muscles of the IL-6 KO mice by 60%.; In summary the results indicate that IL-6 can activate AMPK in rat tissues and that the increase in its concentration contributes to the activation of AMPK in muscle and adipose tissue during exercise. The results also demonstrate that AMPK activity is diminished at rest in muscle and adipose tissue of IL-6 KO mice. They suggest that this initial AMPK deficiency could contribute to the obesity and other manifestations of the metabolic syndrome that occur in these mice as they age. Finally, the results suggest that mitochondrial dysfunction is an early event in white muscle of the IL-6 KO mice. How this relates to the concurrent decreases in AMPK activity at this time and the subsequent increase in its activity at age 14 months remains to be determined. |
