Vascular inflammation, insulin resistance and reduced nitric oxide production precede the onset of peripheral insulin resistance
Open accessAbstract
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. METHODS AND 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.
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Insulin resistance is always associated with impaired NO availability, suggesting a reciprocal relationship between insulin activation and endothelial function.
“insulin resistance is always associated with impaired NO availability, suggesting that a reciprocal relationship exists between insulin activation and endothelial function [50,53].”
From NO-Rich Diet for Lifestyle-Related Diseases (2015) · cites this paper as [53]
NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin-resistant patients.
“NO bioavailability is decreased in animal models of diet-induced obesity and in obese and insulin resistant patients”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [117]
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- Authors
- Kim, F., Pham, M., Maloney, E., Rizzo, N. O., Morton, G. J., Wisse, B. E., Kirk, E. A., Chait, A., & Schwartz, M. W.
- Affiliations
- University of Washington (US)
- Venue
- Arteriosclerosis Thrombosis and Vascular Biology
- Published
- 2008-11
- Volume
- 28
- Issue
- 11
- Pages
- 1982-1988
- ISSN
- 1079-5642 (ISSN-L)
- 1524-4636
- PMC
- PMC2577575
- OpenAlex
- W2123214581
- Cited by
- 364
- References
- 34
- Citations by year
- 2026: 9 · 2025: 13 · 2024: 13 · 2023: 16 · 2022: 22 · 2021: 20 · 2020: 17 · 2019: 17 · 2018: 14 · 2017: 25 · 2016: 25 · 2015: 27 · 2014: 31 · 2013: 35 · 2012: 24
- FWCI
- 13.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Arteriosclerosis Thrombosis and Vascular Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (5r01dk073878-05)
- National Heart, Lung, and Blood Institute (P01HL030086, HL3-0086)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074758, R01DK052989, DK-52989, P01DK068384, R01-DK-073878, DK-073878, DK-68384, P30DK035816)
- Topics
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
- Keywords
- vascular inflammation, insulin resistance, nitric oxide production, endothelial dysfunction, diet-induced obesity, high-fat diet, NF-κB activation, Akt phosphorylation, serum amyloid A, aorta, skeletal muscle, liver, visceral adipose tissue, time course of inflammation
- MeSH terms
- Adipose Tissue, Animals, Body Weight, Dietary Fats, Disease Models, Animal, Endothelium, Vascular, Glucose, Inflammation, Insulin, Insulin Resistance, Liver, Male, Mice, Inbred C57BL, Nitric Oxide, Obesity, Phosphorylation, Time Factors, Vascular Diseases, Signal Transduction, Disease Progression, Muscle, Skeletal, Inflammation Mediators, Adiposity, Mice, I-kappa B Kinase
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