Induction of Adiponectin in Skeletal Muscle by Inflammatory Cytokines: in Vivo and in Vitro Studies

Adiponectin (ApN) is an adipocytokine that plays a fundamental role in energy homeostasis and counteracting inflammation. We examined whether ApN could be induced in a nonadipose tissue, the skeletal muscle, in vivo, and in cultured myotubes in response to lipopolysaccharides or proinflammatory cytokines. We next explored the underlying mechanisms. In vivo, injection of lipopolysaccharides to mice caused, after 24 h, an approximately 10-fold rise in ApN mRNA abundance and a concomitant 70% increase in ApN levels in tibialis anterior muscle. This ApN induction was reproduced in C2C12 myotubes cultured for 48 h with a proinflammatory cytokine combination, interferon-gamma + TNFalpha. This effect occurred in a time- and dose-dependent manner. Several pieces of evidence suggest that nitric oxide (NO) mediates this up-regulation by cytokines in myotubes or muscle. First, ApN was induced in vitro exclusively in the experimental conditions that stimulated NO production. Second, inducible NO synthase mRNA induction or NO production clearly preceded ApN mRNA induction. Third, preventing NO production by inhibitors of the NO synthases, nitro-L-arginine methyl ester or NG-methyl-L-arginine, suppressed the inductive effect of the cytokines in vitro and in vivo. Finally, ApN mRNA induction by cytokines was reproduced in cultured human myotubes. In conclusion, our data provide evidence that adiponectin is up-regulated in vivo and in vitro in human and rodent myotubes in response to inflammatory stimuli. The underlying mechanisms seem to involve a NO-dependent pathway. This overexpression may be viewed as a local antiinflammatory protection and a way to deliver extra energy supplies during inflammation.