Sphingolipid changes do not underlie fatty acid-evoked GLUT4 insulin resistance nor inflammation signals in muscle cells.
Nicolas J PillonScott Frendo-CumboMaya R JacobsonZhi LiuPaul L MilliganHai Hoang BuiJuleen R ZierathPhilip J BilanJoseph T BrozinickAmira KlipPublished in: Journal of lipid research (2018)
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.
Keyphrases
- insulin resistance
- fatty acid
- skeletal muscle
- type diabetes
- adipose tissue
- high fat diet
- metabolic syndrome
- high fat diet induced
- polycystic ovary syndrome
- glycemic control
- single cell
- oxidative stress
- poor prognosis
- signaling pathway
- cell therapy
- induced apoptosis
- cell proliferation
- high glucose
- blood glucose
- diabetic rats
- drug induced
- liver injury
- stem cells
- endothelial cells
- protein kinase
- cell death
- body mass index
- anti inflammatory
- weight loss