title: Distinct patterns of tissue-specific lipid accumulation during the induction of insulin resistance in mice by high-fat feeding.
abstract: OBJECTIVE
  While it is well known that diet-induced obesity causes insulin resistance, the precise mechanisms underpinning the initiation of insulin resistance are unclear. To determine factors that may cause insulin resistance, we have performed a detailed time-course study in mice fed a high-fat diet (HFD).
  
  
  METHODS
  C57Bl/6 mice were fed chow or an HFD from 3 days to 16 weeks and glucose tolerance and tissue-specific insulin action were determined. Tissue lipid profiles were analysed by mass spectrometry and inflammatory markers were measured in adipose tissue, liver and skeletal muscle.
  
  
  RESULTS
  Glucose intolerance developed within 3 days of the HFD and did not deteriorate further in the period to 12 weeks. Whole-body insulin resistance, measured by hyperinsulinaemic-euglycaemic clamp, was detected after 1 week of HFD and was due to hepatic insulin resistance. Adipose tissue was insulin resistant after 1 week, while skeletal muscle displayed insulin resistance at 3 weeks, coinciding with a defect in glucose disposal. Interestingly, no further deterioration in insulin sensitivity was observed in any tissue after this initial defect. Diacylglycerol content was increased in liver and muscle when insulin resistance first developed, while the onset of insulin resistance in adipose tissue was associated with increases in ceramide and sphingomyelin. Adipose tissue inflammation was only detected at 16 weeks of HFD and did not correlate with the induction of insulin resistance.
  
  
  CONCLUSIONS
  HFD-induced whole-body insulin resistance is initiated by impaired hepatic insulin action and exacerbated by skeletal muscle insulin resistance and is associated with the accumulation of specific bioactive lipid species.
authors.affiliation: Diabetes & Obesity Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia.
authors.forename: N
authors.initials: N
authors.lastname: Turner
authors.forename: G M
authors.initials: GM
authors.lastname: Kowalski
authors.forename: S J
authors.initials: SJ
authors.lastname: Leslie
authors.forename: S
authors.initials: S
authors.lastname: Risis
authors.forename: C
authors.initials: C
authors.lastname: Yang
authors.forename: R S
authors.initials: RS
authors.lastname: Lee-Young
authors.forename: J R
authors.initials: JR
authors.lastname: Babb
authors.forename: P J
authors.initials: PJ
authors.lastname: Meikle
authors.forename: G I
authors.initials: GI
authors.lastname: Lancaster
authors.forename: D C
authors.initials: DC
authors.lastname: Henstridge
authors.forename: P J
authors.initials: PJ
authors.lastname: White
authors.forename: E W
authors.initials: EW
authors.lastname: Kraegen
authors.forename: A
authors.initials: A
authors.lastname: Marette
authors.forename: G J
authors.initials: GJ
authors.lastname: Cooney
authors.forename: M A
authors.initials: MA
authors.lastname: Febbraio
authors.forename: C R
authors.initials: CR
authors.lastname: Bruce
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D015153:Blotting, Western; D001823:Body Composition / Q000502:physiology; D059305:Diet, High-Fat / Q000009:adverse effects*; D004797:Enzyme-Linked Immunosorbent Assay; D015309:Glucose Clamp Technique; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction