Abstract
BackgroundAdipose tissue mitochondria have been implicated as key mediators of systemic metabolism. We have shown that IL-6 activates AMPK, a mediator of mitochondrial biogenesis, in adipose tissue; however, IL-6−/− mice fed a high fat diet have been reported to develop insulin resistance. These findings suggest that IL-6 may control adipose tissue mitochondrial content in vivo, and that reductions in adipose tissue mitochondria may be causally linked to the development of insulin resistance in IL-6−/− mice fed a high fat diet. On the other hand, IL-6 has been implicated as a negative regulator of insulin action. Given these discrepancies the purpose of the present investigation was to further evaluate the relationship between IL-6, adipose tissue mitochondrial content and whole body insulin action.Methodology and Principal FindingsIn cultured epididymal mouse adipose tissue IL-6 (75 ng/ml) induced the expression of the transcriptional co-activators PGC-1α and PRC, reputed mediators of mitochondrial biogenesis. Similarly, IL-6 increased the expression of COXIV and CPT-1. These effects were absent in cultured subcutaneous adipose tissue and were associated with lower levels of GP130 and IL-6 receptor alpha protein content. Markers of mitochondrial content were intact in adipose tissue from chow fed IL-6−/− mice. When fed a high fat diet IL-6−/− mice were more glucose and insulin intolerant than controls fed the same diet; however this was not explained by decreases in adipose tissue mitochondrial content or respiration.Conclusions and SignificanceOur findings demonstrate depot-specific differences in the ability of IL-6 to induce PGC-1α and mitochondrial enzymes and demonstrate that IL-6 is not necessary for the maintenance of adipose tissue mitochondrial content in vivo. Moreover, reductions in adipose tissue mitochondria do not explain the greater insulin resistance in IL-6−/− mice fed a high fat diet. These results question the role of adipose tissue mitochondrial dysfunction in the etiology of insulin resistance.
Highlights
PPAR gamma co-activator 1 alpha (PGC-1a) is a transcriptional co-activator that binds to, and co-activates transcription factors leading to the coordinated regulation of mitochondrial and nuclear encoded mitochondrial enzymes [1]
Reductions in adipose tissue mitochondria do not explain the greater insulin resistance in IL-62/2 mice fed a high fat diet. These results question the role of adipose tissue mitochondrial dysfunction in the etiology of insulin resistance
interleukin 6 (IL-6) induces the expression of PGC-1a, PGC-1 related coactivator (PRC) and mitochondrial enzymes in adipose tissue in a depot specific manner
Summary
PPAR gamma co-activator 1 alpha (PGC-1a) is a transcriptional co-activator that binds to, and co-activates transcription factors leading to the coordinated regulation of mitochondrial and nuclear encoded mitochondrial enzymes [1]. When adipose tissue specific PGC-1a knockout mice are fed a high fat diet they are more insulin resistant than their WT littermates [9]. These findings underscore the potential importance of adipose tissue mitochondria in the regulation of fuel homeostasis. We have shown that IL-6 activates AMPK, a mediator of mitochondrial biogenesis, in adipose tissue; IL-62/2 mice fed a high fat diet have been reported to develop insulin resistance. Given these discrepancies the purpose of the present investigation was to further evaluate the relationship between IL-6, adipose tissue mitochondrial content and whole body insulin action
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