Abstract
BackgroundGlyceroneogenesis is an important step in the control of fatty acid re-esterification with PEPCK and PDK4 being identified as key enzymes in this process. We have previously shown that glyceroneogenic enzymes such as PDK4 are rapidly induced in white adipose tissue during exercise. Recent studies have suggested that IL-6 regulates adipose tissue metabolism and gene expression during exercise. Interestingly, IL-6 has been reported to directly decrease PEPCK expression. The purpose of this investigation was to determine the role of IL-6 in modulating the effects of exercise on the expression of glyceroneogenic enzymes in mouse adipose tissue. We hypothesized that the exercise-mediated induction of PDK4 and PEPCK would be greater in adipose tissue from IL-6 deficient mice compared to wild type controls.Methodology and Principle FindingsTreatment of cultured epididymal adipose tissue (eWAT) with IL-6 (150 ng/ml) increased the phosphorylation of AMPK, ACC and STAT3 and induced SOCS3 mRNA levels while decreasing PEPCK and PDK4 mRNA. AICAR decreased the expression of PDK4 and PEPCK. The activation of AMPK by IL-6 was independent of increases in lipolysis. An acute bout of treadmill running (15 meters/minute, 5% incline, 90 minutes) did not induce SOCS3 or increase phosphorylation of STAT3 in eWAT, indicating that IL-6 signalling was not activated. Exercise-induced increases in PEPCK and PDK4 mRNA expression were attenuated in eWAT from IL-6−/− mice in parallel with a greater relative increase in AMPK phosphorylation compared to exercised WT mice. These changes occurred independent of alterations in beta-adrenergic signalling in adipose tissue from IL-6−/− mice.Conclusions and SignificanceOur findings question the role of IL-6 signalling in adipose tissue during exercise and suggest an indirect effect of this cytokine in the regulation of adipose tissue gene expression during exercise.
Highlights
When blood glucose levels are limiting such as during exercise, the breakdown of triglyceride molecules within fat cells is accelerated
interleukin 6 (IL-6) led to a rapid induction of suppressor of cytokine signaling3 (SOCS3) (2 hours 4.7661.26 fold increase*, 6 hours 5.4861.49 fold increase*, 12 hours 4.2461.33 fold increase*, * p,0.05 vs control) a transcriptional target of IL-6 while decreasing Phosphoenolpyruvate carboxykinase (PEPCK) and pyruvate dehydrogenase kinase 4 (PDK4) mRNA expression (Figure 2A)
To determine if decreases in PEPCK and PDK4 resulted in a functional impairment in fatty acid handling we treated cultured adipose tissue with IL-6 (24 hours, 150 ng/ml) and measured the ratio of fatty acid to glycerol released into the media 4 hours following the removal of IL-6
Summary
When blood glucose levels are limiting such as during exercise, the breakdown of triglyceride molecules within fat cells is accelerated. Similar to what has been reported in skeletal muscle [6], we have found that exercise leads to a robust induction of PDK4 in white adipose tissue [7] We demonstrated that this effect was recapitulated by epinephrine and could involve p38 mitogen activated protein kinase (MAPK) [7]. As fatty acid re-esterification is one of the primary drains on ATP levels in adipocytes [9] it is not entirely surprising that AMPK agonists would decrease the expression of enzymes involved in this process. IL-6 has been reported to directly decrease PEPCK expression The purpose of this investigation was to determine the role of IL-6 in modulating the effects of exercise on the expression of glyceroneogenic enzymes in mouse adipose tissue. We hypothesized that the exercise-mediated induction of PDK4 and PEPCK would be greater in adipose tissue from IL-6 deficient mice compared to wild type controls
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