title: Failure of dietary quercetin to alter the temporal progression of insulin resistance among tissues of C57BL/6J mice during the development of diet-induced obesity.
abstract: OBJECTIVE
  High-fat diets produce obesity and glucose intolerance by promoting the development of insulin resistance in peripheral tissues and liver. The present studies sought to identify the initial site(s) where insulin resistance develops using a moderately high-fat diet and to assess whether the bioflavonoid, quercetin, ameliorates progression of this sequence.
  
  
  METHODS
  Four cohorts of male C57BL/6J mice were placed on diets formulated to be low-fat (10% of energy from fat), high-fat (45% of energy from fat) or high-fat plus 1.2% quercetin (wt/wt). After 3 and 8 weeks, cohorts were evaluated using euglycaemic-hyperinsulinaemic clamps, metabolomic analysis of fatty acylcarnitines and acute in vitro assessments of insulin signalling among tissues.
  
  
  RESULTS
  After 3 and 8 weeks, the high-fat diet produced whole-body insulin resistance without altering insulin-dependent glucose uptake in peripheral tissues. The primary defect was impaired suppression of hepatic glucose production by insulin at both times. Quercetin initially exacerbated the effect of high-fat diet by further increasing hepatic insulin resistance, but by 8 weeks insulin resistance and hepatic responsiveness to insulin were similarly compromised in both high-fat groups. The high-fat diet, irrespective of quercetin, increased short-chain fatty acylcarnitines in liver but not in muscle, while reciprocally reducing hepatic long-chain fatty acylcarnitines and increasing them in muscle.
  
  
  CONCLUSIONS
  Failure of insulin to suppress hepatic glucose output is the initial defect that accounts for the insulin resistance that develops after short-term consumption of a high-fat (45% of energy) diet. Hepatic insulin resistance is associated with accumulation of short- and medium-, but not long-chain fatty acylcarnitines. Dietary quercetin does not ameliorate the progression of this sequence.
authors.affiliation: Laboratory of Nutrient Sensing and Adipocyte Signaling, Pennington Biomedical Research Center, 6400 Perkins Road, Baton Rouge, LA 70808, USA.
authors.forename: L K
authors.initials: LK
authors.lastname: Stewart
authors.forename: Z
authors.initials: Z
authors.lastname: Wang
authors.forename: D
authors.initials: D
authors.lastname: Ribnicky
authors.forename: J L
authors.initials: JL
authors.lastname: Soileau
authors.forename: W T
authors.initials: WT
authors.lastname: Cefalu
authors.forename: T W
authors.initials: TW
authors.lastname: Gettys
mesh_terms: D017667:Adipocytes / Q000502:physiology; D000818:Animals; D004041:Dietary Fats / Q000009:adverse effects*; D005247:Feeding Behavior; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000209:etiology / Q000503:physiopathology*; D006946:Hyperinsulinism; D007328:Insulin / Q000502:physiology; D007333:Insulin Resistance / Q000502:physiology*; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000209:etiology / Q000503:physiopathology*; D011794:Quercetin / Q000627:therapeutic use*; D015398:Signal Transduction; D017211:Treatment Failure; D014280:Triglycerides / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D007328:Insulin; D014280:Triglycerides; D011794:Quercetin