Abstract

Membrane-associated semicarbazide-sensitive amine oxidase (SSAO) is mainly present in the media of aorta and in adipose tissue. Recent works have reported that SSAO activation can stimulate glucose transport of fat cells and promote adipose conversion. In this study, the murine 3T3-L1 preadipose cell line was used to investigate SSAO regulation by tumor necrosis factor-α (TNF-α), a cytokine that is synthesized in fat cells and known to be involved in obesity-linked insulin resistance. SSAO mRNA and protein levels, and enzyme activity were decreased by TNF-α in a dose- and time-dependent manner, without any change of SSAO affinity for substrates or inhibitors. SSAO inhibition caused by TNF-α was spontaneously reversed along the time after TNF-α removal. The decrease in SSAO expression also occurred in white adipose tissue of C57BL/6 mice treated with mTNF-α. Overall, we demonstrated that reduction in SSAO expression induced by the cytokine had marked repercussions on amine-stimulated glucose transport, in a dose- and time-dependent manner. This effect was more pronounced than the inhibiting effect of TNF-α on insulin-stimulated glucose transport. Moreover, the peroxisome proliferator-activated receptor γ agonists thiazolidinediones did not reverse either TNF-α effect on amine-sensitive glucose transport or the inhibition of SSAO activity, whereas they antagonized TNF-α effects on insulin-sensitive glucose transport. These results demonstrate that TNF-α can strongly down-regulate SSAO expression and activity, and through this mechanism can dramatically reduce amine-stimulated glucose transport. This suggests a potential role of this regulatory process in the pathogenesis of glucose homeostasis dysregulations observed during diseases accompanied by TNF-α overproduction, such as cachexia or obesity.