title: Vascular inflammation, insulin resistance, and reduced nitric oxide production precede the onset of peripheral insulin resistance.
abstract: OBJECTIVE
  Obesity causes inflammation and insulin resistance in the vasculature as well as in tissues involved in glucose metabolism such as liver, muscle, and adipose tissue. To investigate the relative susceptibility of vascular tissue to these effects, we determined the time course over which inflammation and insulin resistance develops in various tissues of mice with diet-induced obesity (DIO) and compared these tissue-based responses to changes in circulating inflammatory markers.
  
  
  RESULTS
  Adult male C57BL/6 mice were fed either a control low-fat diet (LF; 10% saturated fat) or a high-fat diet (HF, 60% saturated fat) for durations ranging between 1 to 14 weeks. Cellular inflammation and insulin resistance were assessed by measuring phospho-IkappaBalpha and insulin-induced phosphorylation of Akt, respectively, in extracts of thoracic aorta, liver, skeletal muscle, and visceral fat. As expected, HF feeding induced rapid increases of body weight, fat mass, and fasting insulin levels compared to controls, each of which achieved statistical significance within 4 weeks. Whereas plasma markers of inflammation became elevated relatively late in the course of DIO (eg, serum amyloid A [SAA], by Week 14), levels of phospho-IkappaBalpha in aortic lysates were elevated by 2-fold within the first week. The early onset of vascular inflammation was accompanied by biochemical evidence of both endothelial dysfunction (reduced nitric oxide production; induction of intracellular adhesion molecule-1 and vascular cell adhesion molecule-1) and insulin resistance (impaired insulin-induced phosphorylation of Akt and eNOS). Although inflammation and insulin resistance were also detected in skeletal muscle and liver of HF-fed animals, these responses were observed much later (between 4 and 8 weeks of HF feeding), and they were not detected in visceral adipose tissue until 14 weeks.
  
  
  CONCLUSIONS
  During obesity induced by HF feeding, inflammation and insulin resistance develop in the vasculature well before these responses are detected in muscle, liver, or adipose tissue. This observation suggests that the vasculature is more susceptible than other tissues to the deleterious effects of nutrient overload.
authors.affiliation: Department of Medicine, Diabetes and Obesity Center of Excellence, University of Washington, Seattle, WA 98104, USA. fkim@u.washington.edu
authors.forename: Francis
authors.initials: F
authors.lastname: Kim
authors.forename: Matilda
authors.initials: M
authors.lastname: Pham
authors.forename: Ezekiel
authors.initials: E
authors.lastname: Maloney
authors.forename: Norma O
authors.initials: NO
authors.lastname: Rizzo
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.forename: Brent E
authors.initials: BE
authors.lastname: Wisse
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Kirk
authors.forename: Alan
authors.initials: A
authors.lastname: Chait
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism / Q000503:physiopathology; D050154:Adiposity; D000818:Animals; D001835:Body Weight; D004041:Dietary Fats; D004195:Disease Models, Animal; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000503:physiopathology; D005947:Glucose / Q000378:metabolism*; D051550:I-kappa B Kinase / Q000378:metabolism; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D018836:Inflammation Mediators / Q000097:blood; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance; D008099:Liver / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism*; D009765:Obesity / Q000150:complications* / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D010766:Phosphorylation; D015398:Signal Transduction; D013997:Time Factors; D014652:Vascular Diseases / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology
chemical_list: D004041:Dietary Fats; D018836:Inflammation Mediators; D007328:Insulin; D009569:Nitric Oxide; D051550:I-kappa B Kinase; D005947:Glucose
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