HMGB1 mediates sidestream cigarette smoke‐induced metabolic disruption

Abstract

High‐mobility group box 1 (HMGB1) is a protein released in response to various noxious stimuli, including cigarette smoke. Its pro‐inflammatory actions generally occur through activation of prominent pattern recognition receptors, namely RAGE and TLR4. We have previously found that both RAGE and TLR4 activation disrupt mitochondrial physiology and insulin signaling in skeletal muscle via ceramide accrual. Thus, the purpose of these studies was to determine whether HMGB1 is sufficient in mediating the metabolic disruption observed with sidestream smoke exposure and whether this effect is dependent on altered ceramide metabolism. Initially, we confirmed that HMGB1 was increased in skeletal muscle with chronic sidestream cigarette smoke exposure. To test the effect of HMGB1 directly, we found that HMGB1 treatment increased muscle cell ceramide levels and disrupted mitochondrial and insulin function, an effect that was alleviated with ceramide inhibition. Moreover, ceramide inhibition partially prevented reduced insulin and glucose tolerance in mice, and protected mitochondrial function in skeletal muscle. Altogether, these data suggest that HMGB1 may be a relevant signaling mediator in the metabolic response to cigarette smoke exposure.