Transgenic Restoration of Long-Chain n-3 Fatty Acids in Insulin Target Tissues Improves Resolution Capacity and Alleviates Obesity-Linked Inflammation and Insulin Resistance in High-Fat–Fed Mice
Open Access
- 14 September 2010
- journal article
- research article
- Published by American Diabetes Association in Diabetes
- Vol. 59 (12), 3066-3073
- https://doi.org/10.2337/db10-0054
Abstract
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.This publication has 32 references indexed in Scilit:
- Cyclooxygenase-2 generates anti-inflammatory mediators from omega-3 fatty acidsNature Chemical Biology, 2010
- Transgenic expression of n‐3 fatty acid desaturase (fat‐1) in C57/BL6 mice: Effects on glucose homeostasis and body weightJournal of Cellular Biochemistry, 2009
- Obesity‐induced insulin resistance and hepatic steatosis are alleviated by ω‐3 fatty acids: a role for resolvins and protectinsThe FASEB Journal, 2009
- Maresins: novel macrophage mediators with potent antiinflammatory and proresolving actionsThe Journal of Experimental Medicine, 2008
- Obese Mice Lacking Inducible Nitric Oxide Synthase Are Sensitized to the Metabolic Actions of Peroxisome Proliferator–Activated Receptor-γ AgonismDiabetes, 2008
- Endogenous pro‐resolving and anti‐inflammatory lipid mediators: a new pharmacologic genusBritish Journal of Pharmacology, 2008
- Resolvin E1 and protectin D1 activate inflammation-resolution programmesNature, 2007
- Long‐chain omega‐3 fatty acids regulate bovine whole‐body protein metabolism by promoting muscle insulin signalling to the Akt–mTOR–S6K1 pathway and insulin sensitivityThe Journal of Physiology, 2007
- Inflammation and metabolic disordersNature, 2006
- Dietary Omega-3 Fatty Acid Intake and Cardiovascular RiskThe American Journal of Cardiology, 2006