Cigarette smoking blocks the benefit from reduced weight gain for insulin action by shifting lipids deposition to muscle.

Cigarette smoking (CS) is known to reduce body weight and this often masks its real effect on insulin action. The present study tested the hypothesis that CS can divert lipid deposition to muscles to offset the supposed benefit of reduced body weight gain on insulin signalling in this major site for glucose tolerance (or insulin action). The study was conducted in mice exposed to chronic CS followed by either a chow (CH) diet or a high-fat (HF) diet. CS increased triglyceride (TG) levels in both plasma and muscle despite a reduced body weight gain and adiposity. CS led to glucose intolerance in CH-fed mice and they retained the glucose intolerance that was induced by the HF diet. In adipose tissue, CS increased macrophage infiltration and the mRNA expression of TNFα but suppressed the protein expression of adipose triglyceride lipase and PPARγ. While CS increased hormone-sensitive lipase and suppressed the mRNA expression of leptin, these effects were blunted in HF-fed mice. These results imply that CS impairs insulin signalling in skeletal muscle via accumulated intramuscular lipids from lipolysis and lipodystrophy of adipose tissues. This may explain why smokers may not benefit from insulin sensitising effects of reduced body weight gain.

The role of de novo protein synthesis and SIRT1 in ER stress-induced Atf4 and Chop mRNA expression in mammalian cells.

Endoplasmic reticulum (ER) stress and the activation of the unfolded protein response (UPR) have been implicated in the pathogenesis of many common human diseases. Integral to the UPR and an important determinant in cell fate is the expression of the pro-apoptotic transcription factor C/EBP homologous protein (CHOP). This is promoted by activating transcription factor 4 (ATF4) whose expression is rapidly up-regulated in response to ER stress through an eIF2α phosphorylation-dependent increase in protein synthesis. Our data demonstrates that this ER stress-induced increase in ATF4 and CHOP expression is initiated by an increase in Atf4 and Chop mRNA, which is also dependent upon eIF2α phosphorylation. Despite being dependent on eIF2α phosphorylation, we provide evidence that these increases in Atf4 and Chop mRNA expression may occur independently of de novo protein synthesis. Moreover, we show that ER stress-induced Chop mRNA expression is exacerbated by Sirtuin-1 (SIRT1) inhibition indicating that changes in the energy status of the cell may play an important role in its regulation. This work highlights and extends previous findings, and provides important new insights into the mechanism of ER stress-induced expression of Atf4 and Chop mRNA that clearly warrants further investigation.