Extremely rapid increase in fatty acid transport and intramyocellular lipid accumulation but markedly delayed insulin resistance after high fat feeding in rats

Arend Bonen*, Swati S. Jain, Laelie A. Snook, Xiao-Xia Han, Yuko Yoshida, Kathryn H. Buddo, James S. Lally, Elizabeth D. Pask, Sabina Paglialunga, Marie-Soleil Beaudoin, Jan F. C. Glatz, Joost J. F. P. Luiken, Ewa Harasim, David C. Wright, Adrian Chabowski, Graham P. Holloway

*Corresponding author for this work

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Abstract

Aims/hypothesis The mechanisms for diet-induced intramyocellular lipid accumulation and its association with insulin resistance remain contentious. In a detailed time-course study in rats, we examined whether a high-fat diet increased intramyocellular lipid accumulation via alterations in fatty acid translocase (FAT/CD36)-mediated fatty acid transport, selected enzymes and/or fatty acid oxidation, and whether intramyocellular lipid accretion coincided with the onset of insulin resistance. Methods We measured, daily (on days 1-7) and/or weekly (for 6 weeks), the diet-induced changes in circulating substrates, insulin, sarcolemmal substrate transporters and transport, selected enzymes, intramyocellular lipids, mitochondrial fatty acid oxidation and basal and insulin-stimulated sarcolemmal GLUT4 and glucose transport. We also examined whether upregulating fatty acid oxidation improved glucose transport in insulin-resistant muscles. Finally, in Cd36-knockout mice, we examined the role of FAT/CD36 in intramyocellular lipid accumulation, insulin sensitivity and diet-induced glucose intolerance. Results Within 2-3 days, diet-induced increases occurred in insulin, sarcolemmal FAT/CD36 (but not fatty acid binding protein [FABPpm] or fatty acid transporter [FATP]1 or 4), fatty acid transport and intramyocellular triacylglycerol, diacylglycerol and ceramide, independent of enzymatic changes or muscle fatty acid oxidation. Diet-induced increases in mitochondria and mitochondrial fatty acid oxidation and impairments in insulin-stimulated glucose transport and GLUT4 translocation occurred much later (a parts per thousand yen21 days). FAT/CD36 ablation impaired insulin-stimulated fatty acid transport and lipid accumulation, improved insulin sensitivity and prevented diet-induced glucose intolerance. Increasing fatty acid oxidation in insulin-resistant muscles improved glucose transport. Conclusions/interpretations High-fat feeding rapidly increases intramyocellular lipids (in 2-3 days) via insulin-mediated upregulation of sarcolemmal FAT/CD36 and fatty acid transport. The 16-19 day delay in the onset of insulin resistance suggests that additional mechanisms besides intramyocellular lipids contribute to this pathology.
Original languageEnglish
Pages (from-to)2381-2391
JournalDiabetologia
Volume58
Issue number10
DOIs
Publication statusPublished - Oct 2015

Keywords

  • Ceramide
  • Diacylglycerol
  • Fatty acid oxidation
  • Glucose transport
  • GLUT4
  • Insulin resistance
  • Mitochondria
  • Muscle
  • PGC-1 alpha
  • Triacylglycerol

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