title: 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.
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Mikayla O
authors.initials: MO
authors.lastname: Thatcher
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Tippetts
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Nelson
authors.affiliation: Department of Chemistry and Biochemistry, Brigham Young University, Provo, Utah.
authors.forename: Adam C
authors.initials: AC
authors.lastname: Swensen
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Duane R
authors.initials: DR
authors.lastname: Winden
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Melissa E
authors.initials: ME
authors.lastname: Hansen
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Madeline C
authors.initials: MC
authors.lastname: Anderson
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Ian E
authors.initials: IE
authors.lastname: Johnson
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: James P
authors.initials: JP
authors.lastname: Porter
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and.
authors.forename: Paul R
authors.initials: PR
authors.lastname: Reynolds
authors.affiliation: Department of Physiology and Developmental Biology, Brigham Young University, Provo, Utah; and benjamin_bikman@byu.edu.
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Bikman
mesh_terms: D000818:Animals; D002241:Carbohydrates; D019069:Cell Respiration; D002518:Ceramides / Q000378:metabolism*; D059305:Diet, High-Fat; D005229:Fatty Acids, Monounsaturated / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D015398:Signal Transduction; D012906:Smoke / Q000009:adverse effects*; D014026:Nicotiana / Q000633:toxicity*
chemical_list: D002241:Carbohydrates; D002518:Ceramides; D005229:Fatty Acids, Monounsaturated; D007328:Insulin; D012906:Smoke; C001996:thermozymocidin
keywords: ceramide; cigarette smoke; insulin resistance; metabolic disruption; mitochondria