title: Extremely rapid increase in fatty acid transport and intramyocellular lipid accumulation but markedly delayed insulin resistance after high fat feeding in rats.
abstract: OBJECTIVE
  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
  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.
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1. arend.bonen@gmail.com.
authors.forename: Arend
authors.initials: A
authors.lastname: Bonen
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Swati S
authors.initials: SS
authors.lastname: Jain
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Laelie A
authors.initials: LA
authors.lastname: Snook
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Xiao-Xia
authors.initials: XX
authors.lastname: Han
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Yoshida
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Kathryn H
authors.initials: KH
authors.lastname: Buddo
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: James S
authors.initials: JS
authors.lastname: Lally
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Elizabeth D
authors.initials: ED
authors.lastname: Pask
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Sabina
authors.initials: S
authors.lastname: Paglialunga
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Marie-Soleil
authors.initials: MS
authors.lastname: Beaudoin
authors.affiliation: Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands.
authors.forename: Jan F C
authors.initials: JF
authors.lastname: Glatz
authors.affiliation: Department of Molecular Genetics, Maastricht University, Maastricht, the Netherlands.
authors.forename: Joost J F P
authors.initials: JJ
authors.lastname: Luiken
authors.affiliation: Department of Physiology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Ewa
authors.initials: E
authors.lastname: Harasim
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: David C
authors.initials: DC
authors.lastname: Wright
authors.affiliation: Department of Physiology, Medical University of Bialystok, Bialystok, Poland.
authors.forename: Adrian
authors.initials: A
authors.lastname: Chabowski
authors.affiliation: Department of Human Health & Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.
authors.forename: Graham P
authors.initials: GP
authors.lastname: Holloway
mesh_terms: D000818:Animals; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005227:Fatty Acids / Q000378:metabolism*; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D032342:Muscle Cells / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018955:CD36 Antigens; D050556:Fatty Acid-Binding Proteins; D005227:Fatty Acids; D051275:Glucose Transporter Type 4; C495694:Slc2a4 protein, rat; D005947:Glucose
keywords: Ceramide; Diacylglycerol; Fatty acid oxidation; GLUT4; Glucose transport; Insulin resistance; Mitochondria; Muscle; PGC-1α; Triacylglycerol