Sphingolipid changes do not underlie fatty acid-evoked GLUT4 insulin resistance nor inflammation signals in muscle cells.

Abstract

Ceramides contribute to obesity-linked insulin resistance and inflammation in vivo, but whether this is a cell-autonomous phenomenon is debated, particularly in muscle, which dictates whole-body glucose uptake. We comprehensively analyzed lipid species produced in response to fatty acids and examined the consequence to insulin resistance and pro-inflammatory pathways. L6 myotubes were incubated with BSA-adsorbed palmitate or palmitoleate in the presence of myriocin, fenretinide, or fumonisin B1. Lipid species were determined by lipidomic analysis. Insulin sensitivity was scored by Akt phosphorylation and glucose transporter 4 (GLUT4) translocation, while pro-inflammatory indices were estimated by IκBα degradation and cytokine expression. Palmitate, but not palmitoleate, had mild effects on Akt phosphorylation but significantly inhibited insulin-stimulated GLUT4 translocation and increased expression of pro-inflammatory cytokines Il6 and Ccl2 Ceramides, hexosylceramides, and sphingosine-1-phosphate significantly heightened by palmitate correlated negatively with insulin sensitivity and positively with pro-inflammatory indices. Inhibition of sphingolipid pathways led to marked changes in cellular lipids, but did not prevent palmitate-induced impairment of insulin-stimulated GLUT4 translocation, suggesting that palmitate-induced accumulation of deleterious lipids and insulin resistance are correlated but independent events in myotubes. We propose that muscle cell-endogenous ceramide production does not evoke insulin resistance and that deleterious effects of ceramides in vivo may arise through ancillary cell communication.

• Authors: Nicolas J Pillon, Scott Frendo-Cumbo, Maya R Jacobson, Zhi Liu, Paul L Milligan, Hai Hoang Bui, Juleen R Zierath, Philip J Bilan, Joseph T Brozinick, Amira Klip
• Journal: Journal of lipid research (J Lipid Res) Vol. 59 Issue 7 Pg. 1148-1163 (07 2018) ISSN: 1539-7262 [Electronic] United States
• PMID: 29794037 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2018 by the American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• Fatty Acids
• Glucose Transporter Type 4
• NF-kappa B
• Sphingolipids
• Palmitic Acid

Topics

• Animals
• Fatty Acids (metabolism)
• Glucose Transporter Type 4 (metabolism)
• Inflammation (metabolism, pathology)
• Insulin Resistance
• Muscle Fibers, Skeletal (drug effects, metabolism, pathology)
• Muscles (metabolism, pathology)
• NF-kappa B (metabolism)
• Palmitic Acid (pharmacology)
• Protein Transport (drug effects)
• Rats
• Signal Transduction (drug effects)
• Sphingolipids (metabolism)