Fenofibrate Reverses Palmitate Induced Impairment in Glucose Uptake in Skeletal Muscle Cells by Preventing Cytosolic Ceramide Accumulation

Cell Physiol Biochem. 2015;37(4):1315-28. doi: 10.1159/000430399. Epub 2015 Oct 22.

Abstract

Backgrounds/aims: The lipid induced insulin resistance is a major pathophysiologic mechanism underlying glucose intolerance of varying severity. PPARα-agonists are proven as effective hypolipidemic agents. The aim of this study was to see if impaired glucose uptake in palmitate treated myotubes is reversed by fenofibrate.

Methods: Palmitate-treated myotubes were used as a model for insulin resistance, impaired glucose uptake, fatty acid oxidation and ceramide synthesis. mRNA levels of CPT1 and CPT2 were determined by PCR array and Q-PCR.

Results: The incubation of myotubes with 750 uM palmitate not only reduced glucose uptake but also impaired fatty acid oxidation and cytosolic ceramide accumulation. Palmitate upregulated CPT1b expression in L6 myotubes, while CPT2 expression level remained unchanged. The altered stoichiometric ratio between the two CPT isoforms led to reduced fatty acid oxidation (FAO), ceramide accumulation and impaired glucose uptake, whereas administration of 200 µM fenofibrate significantly reversed the above abnormalities by increasing CPT2 mRNA levels and restoring CPT1b to CPT2 ratio.

Conclusion: Palmitate-induced alteration in the stoichiometric ratio of mitochondrial CPT isoforms leads to incomplete FAO and enhanced cytosolic ceramide accumulation that lead to insulin resistance. Fenofibrate ameliorated insulin resistance by restoring the altered stoichiometry by upregulating CPT2 and preventing, cytoplasmic ceramide accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carnitine O-Palmitoyltransferase / genetics
  • Carnitine O-Palmitoyltransferase / metabolism
  • Cell Line
  • Ceramides / metabolism*
  • Cytosol / metabolism
  • Diet, High-Fat
  • Fatty Acids / metabolism*
  • Fenofibrate / pharmacology*
  • Glucose / metabolism*
  • Glucose Transporter Type 4 / metabolism
  • Hypolipidemic Agents / pharmacology*
  • Insulin Resistance
  • Lipid Peroxidation
  • Mice
  • Mitochondria / metabolism
  • Muscle, Skeletal / cytology
  • Muscle, Skeletal / drug effects
  • Muscle, Skeletal / metabolism
  • Palmitates / pharmacology*
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • RNA, Messenger / metabolism
  • Rats

Substances

  • Ceramides
  • Fatty Acids
  • Glucose Transporter Type 4
  • Hypolipidemic Agents
  • Palmitates
  • Protein Isoforms
  • RNA, Messenger
  • Carnitine O-Palmitoyltransferase
  • Glucose
  • Fenofibrate