Ceramides mediate cigarette smoke-induced metabolic disruption in mice

Abstract

Cigarette smoke exposure increases lung ceramide biosynthesis and alters metabolic function. We hypothesized that ceramides are released from the lung during cigarette smoke exposure and result in elevated skeletal muscle ceramide levels, resulting in insulin resistance and altered mitochondrial respiration. Employing cell and animal models, we explored the effect of cigarette smoke on muscle cell insulin signaling and mitochondrial respiration. Muscle cells were treated with conditioned medium from cigarette smoke extract (CSE)-exposed lung cells, followed by analysis of ceramides and assessment of insulin signaling and mitochondrial function. Mice were exposed to daily cigarette smoke and a high-fat, high-sugar (HFHS) diet with myriocin injections to inhibit ceramide synthesis. Comparisons were conducted between these mice and control animals on standard diets in the absence of smoke exposure and myriocin injections. Muscle cells treated with CSE-exposed conditioned medium were completely unresponsive to insulin stimulation, and mitochondrial respiration was severely blunted. These effects were mitigated when lung cells were treated with the ceramide inhibitor myriocin prior to and during CSE exposure. In mice, daily cigarette smoke exposure and HFHS diet resulted in insulin resistance, which correlated with elevated ceramides. Although myriocin injection was protective against insulin resistance with either smoke or HFHS, it was insufficient to prevent insulin resistance with combined CS and HFHS. However, myriocin injection restored muscle mitochondrial respiration in all treatments. Ceramide inhibition prevents metabolic disruption in muscle cells with smoke exposure and may explain whole body insulin resistance and mitochondrial dysfunction in vivo.

β-Hydroxybutyrate improves β-cell mitochondrial function and survival

“…Cells were prepared for mitochondrial respiration as described previously 27,28 before being transferred to respirometer chambers using the Oroboros O2K oxygraph. Electron flow through complex I was supported by glutamate + malate (10 mM and 2 mM, respectively) to determine leak oxygen consumption (GM L ).…”

Plausible Roles for RAGE in Conditions Exacerbated by Direct and Indirect (Secondhand) Smoke Exposure

“…Due to the obvious challenges of determining causality of a cigarette smoke-insulin resistance interaction, most of the findings in humans are correlational in nature [159,160], though limited data exist to establish [161,162] that cigarette smoke exposure increases insulin resistance. Typified by a reduced ability of insulin to elicit action at cells throughout the body, as well as general hyperinsulinemia, insulin resistance is at the heart of most cardiometabolic disorders, such as hypertension [163,164], atherosclerosis [163], dyslipidemia [165], cardiomyopathy [166], and more [167,168].…”

“…In particular, cigarette smoke pathologically alters sphingolipid metabolism, resulting in the accrual of ceramides, the backbone of higher-order sphingolipids, in heart [162] and skeletal muscle [178]—two key insulin-responsive tissues. Ceramide accrual in these tissues resulted in substantial disruption of mitochondrial function, including alterations in morphology and electron transport.…”

A Standardized Method for the Preparation of a Gas Phase Extract of Cigarette Smoke

“…In the case of whole cigarette smoke extract and the tar phase extract, concentrations have been expressed in terms of the concentrations of endogenous substances such as nicotine [27][28][29] : the amount of these substances is relatively easy to determine using gas chromatography or the weight trapped on the Cambridge filter, respectively. However, in the case of nicotine-and tar-free CSE, it is difficult to express its concentration, because it does not contain appropriate endogenous substances like nicotine and tar.…”