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

AbstractAIMS/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 (≥21 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.
AuthorsArend 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
JournalDiabetologia (Diabetologia) Vol. 58 Issue 10 Pg. 2381-91 (Oct 2015) ISSN: 1432-0428 [Electronic] Germany
PMID26197708 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CD36 Antigens
  • Fatty Acid-Binding Proteins
  • Fatty Acids
  • Glucose Transporter Type 4
  • Slc2a4 protein, rat
  • Glucose
Topics
  • Animals
  • CD36 Antigens (genetics, metabolism)
  • Diet, High-Fat
  • Fatty Acid-Binding Proteins (metabolism)
  • Fatty Acids (metabolism)
  • Glucose (metabolism)
  • Glucose Transporter Type 4 (metabolism)
  • Insulin Resistance (genetics, physiology)
  • Lipid Metabolism (genetics, physiology)
  • Male
  • Mitochondria (metabolism)
  • Muscle Cells (metabolism)
  • Muscle, Skeletal (metabolism)
  • Rats
  • Rats, Sprague-Dawley

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