Journal
DIABETES
Volume 59, Issue 12, Pages 3066-3073Publisher
AMER DIABETES ASSOC
DOI: 10.2337/db10-0054
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Funding
- Canadian Diabetes Association
- Canadian Institutes of Health Research (CIHR)
- National Institutes of Health [R01-CA-113605]
- Fonds de la Recherche en Sante du Quebec
- Grants-in-Aid for Scientific Research [21370051] Funding Source: KAKEN
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OBJECTIVE The catabasis of inflammation is an active process directed by n-3 derived pro-resolving lipid mediators. We aimed to determine whether high-fat (HF) diet-induced n-3 deficiency compromises the resolution capacity of obese mice and thereby contributes to obesity-linked inflammation and insulin resistance. RESEARCH DESIGN AND METHODS We used transgenic expression of the fat-1 n-3 fatty acid desaturase from C. elegans to endogenously restore n-3 fatty acids in HF-fed mice. After 8 weeks on HF or chow diets, wild-type and fat-1 transgenic mice were subjected to insulin and glucose tolerance tests and a resolution assay was performed. Metabolic tissues were then harvested for biochemical analyses. RESULTS We report that the n-3 docosanoid resolution mediator protectin D1 is lacking in muscle and adipose tissue of HF-fed wild-type mice. Accordingly, HF-fed wild-type mice have an impaired capacity to resolve an acute inflammatory response and display elevated adipose macrophage accrual and chemokine/cytokine expression. This is associated with insulin resistance and higher activation of iNOS and JNK in muscle and liver. These defects are reversed in HF-fed fat-1 mice, in which the biosynthesis of this important n-3 docosanoid resolution mediator is improved. Importantly, transgenic restoration of n-3 fatty acids prevented obesity-linked inflammation and insulin resistance in HF-fed mice without altering food intake, weight gain, or adiposity. CONCLUSIONS We conclude that inefficient biosynthesis of n-3 resolution mediators in muscle and adipose tissue contributes to the maintenance of chronic inflammation in obesity and that these novel lipids offer exciting potential for the treatment of insulin resistance and diabetes. Diabetes 59:3066-3073, 2010
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