AICAR inhibits ceramide biosynthesis in skeletal muscle

Erickson, Katherine; Smith, Melissa; Anthonymuthu, Tamil S.; Evanson, Michael J; Brassfield, Eric S; Hodson, Aimee E.; Bressler, M Andrew; Tucker, Braden J; Thatcher, Mikayla O.; Prince, John T.; Hancock, Chad R.; Bikman, Benjamin T.

doi:10.1186/1758-5996-4-45

Cited by 25 publications

(22 citation statements)

References 37 publications

(44 reference statements)

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“…The most prominent identified changes were in ceramides (identification confirmed by matching accurate mass and retention time with external standard), which decreased significantly with AICAR treatment ( Fig 6E ). We also found that concentrations of serine were reduced in a dose-dependent manner after the addition of AICAR ( S4 Fig ) consistent with the previously described inhibition of serine palmitoyltransferase II [ 33 ].…”

Section: Resultssupporting

confidence: 91%

Metabolomics Analysis Reveals that AICAR Affects Glycerolipid, Ceramide and Nucleotide Synthesis Pathways in INS-1 Cells

et al. 2015

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AMPK regulates many metabolic pathways including fatty acid and glucose metabolism, both of which are closely associated with insulin secretion in pancreatic β-cells. Insulin secretion is regulated by metabolic coupling factors such as ATP/ADP ratio and other metabolites generated by the metabolism of nutrients such as glucose, fatty acid and amino acids. However, the connection between AMPK activation and insulin secretion in β-cells has not yet been fully elucidated at a metabolic level. To study the effect of AMPK activation on glucose stimulated insulin secretion, we applied the pharmacological activator 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) to an INS-1 (832/13) β-cell line. We measured the change in 66 metabolites in the presence or absence of AICAR using different stable isotopic labeled nutrients to probe selected pathways. AMPK activation by AICAR increased basal insulin secretion and reduced the glucose stimulation index. Although ATP/ADP ratios were not strongly affected by AICAR, several other metabolites and pathways important for insulin secretion were affected by AICAR treatment including long-chain CoAs, malonyl-CoA, 3-hydroxy-3 methylglutaryl CoA, diacylglycerol, and farnesyl pyrophosphate. Tracer studies using 13C-glucose revealed lower glucose flux in the purine and pyrimidine pathway and in the glycerolipid synthesis pathway. Untargeted metabolomics revealed reduction in ceramides caused by AICAR that may explain the beneficial role of AMPK in protecting β-cells from lipotoxicity. Taken together, the results provide an overall picture of the metabolic changes associated with AICAR treatment and how it modulates insulin secretion and β-cell survival.

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Section: Resultssupporting

confidence: 91%

Metabolomics Analysis Reveals that AICAR Affects Glycerolipid, Ceramide and Nucleotide Synthesis Pathways in INS-1 Cells

et al. 2015

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“…Protein quantification and quantitative real-time PCR. Protein and message were quantified as described previously (21,47). Primers were used as listed previously (21).…”

Section: Methodsmentioning

confidence: 99%

“…Protein and message were quantified as described previously (21,47). Primers were used as listed previously (21). ␤-Actin reactions were performed side by side with every sample analyzed.…”

Section: Methodsmentioning

confidence: 99%

Ceramides mediate cigarette smoke-induced metabolic disruption in mice

Thatcher

Tippetts

Nelson

et al. 2014

American Journal of Physiology-Endocrinology and Metabolism

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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.

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“…After the addition of sample buffer, samples were resolved by SDS/PAGE (10% gel), transferred onto nitrocellulose membranes, and immunoblotted using methods described previously [31]. After incubation with primary antibody, blots were incubated with an HRP- (horseradish peroxidase-) conjugated secondary antibody.…”

Section: Methodsmentioning

confidence: 99%

Insulin Increases Ceramide Synthesis in Skeletal Muscle

Hansen

Tippetts

Anderson

et al. 2014

Journal of Diabetes Research

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Aims. The purpose of this study was to determine the effect of insulin on ceramide metabolism in skeletal muscle. Methods. Skeletal muscle cells were treated with insulin with or without palmitate for various time periods. Lipids (ceramides and TAG) were isolated and gene expression of multiple biosynthetic enzymes were quantified. Additionally, adult male mice received daily insulin injections for 14 days, followed by muscle ceramide analysis. Results. In muscle cells, insulin elicited an increase in ceramides comparable to palmitate alone. This is likely partly due to an insulin-induced increase in expression of multiple enzymes, particularly SPT2, which, when knocked down, prevented the increase in ceramides. In mice, 14 days of insulin injection resulted in increased soleus ceramides, but not TAG. However, insulin injections did significantly increase hepatic TAG compared with vehicle-injected animals. Conclusions. This study suggests that insulin elicits an anabolic effect on sphingolipid metabolism in skeletal muscle, resulting in increased ceramide accumulation. These findings reveal a potential mechanism of the deleterious consequences of the hyperinsulinemia that accompanies insulin resistance and suggest a possible novel therapeutic target to mitigate its effects.

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AICAR inhibits ceramide biosynthesis in skeletal muscle

Cited by 25 publications

References 37 publications

Metabolomics Analysis Reveals that AICAR Affects Glycerolipid, Ceramide and Nucleotide Synthesis Pathways in INS-1 Cells

Metabolomics Analysis Reveals that AICAR Affects Glycerolipid, Ceramide and Nucleotide Synthesis Pathways in INS-1 Cells

Ceramides mediate cigarette smoke-induced metabolic disruption in mice

Insulin Increases Ceramide Synthesis in Skeletal Muscle

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