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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.

White PJ, Arita M, Taguchi R, Kang JX, Marette A - Diabetes (2010)

Bottom Line: The catabasis of inflammation is an active process directed by n-3 derived pro-resolving lipid mediators.Metabolic tissues were then harvested for biochemical analyses.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Faculty of Medicine, Cardiology axe, Quebec Heart and Lung Institute, CHUQ Research Centre, and INAF, Laval University, Quebec, Canada.

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.

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Related in: MedlinePlus

HF feeding reduces n-3 availability for resolution mediator synthesis. A: 8 weeks of HF feeding raised but fat-1 (F1) transgenesis restored the long-chain n-6:n-3 ratio in membrane phospholipids of muscle, liver, and epididymal adipose tissue. C, standard laboratory chow; AA, arachidonic acid (20:4 n-6); EPA, eicosapentaenoic acid (20:5 n-3); DPA, docosapentaenoic acid (22:5 n-3); DHA, docosahexaenoic acid (22:6 n-3). Data are mean ± SEM (n = 3). **P < 0.01 versus WTC; ***P < 0.001 versus WTC; †P < 0.05 versus WTHF; ††P < 0.01 versus WTHF. B: Comparison of n-3 docosanoid and eicosanoid biosynthetic pathways by LC-MS/MS in muscle, liver, and epididymal adipose tissue of HF-fed mice revealed that the docosanoid biosynthetic pathway has greater flux in metabolic tissues. Above left schematic diagram of docosanoid biosynthetic pathway showing the biosynthetic marker 17-HDoHE and PD1 (10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid [28]) as well as the immediate PD1 precursor 17-HpDoHE. At right, the eicosanoid pathway showing 18-HEPE and RvE1 (5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA [29]). ND indicates not detected. Data are mean ± SEM (n = 9–14). *P < 0.05, **P < 0.01, ***P < 0.001 versus 17-HDoHE. C: Representative LC-MS/MS spectra for 17-HDoHE, PD1, and 18-HEPE; retention times were 22.6, 18.2, and 20.6 min, respectively. D: Comparison of n-3 docosanoid and eicosanoid biosynthetic pathway activity by LC-MS/MS in muscle, liver, and epididymal adipose tissue of HF-fed wild-type and F1 mice reveals increased levels of docosanoid resolution mediator synthesis in muscle and adipose tissue of F1 mice compared with wild-type mice. Data are mean ± SEM (n = 6–10). *P < 0.05 versus WTHF. (A high-quality color representation of this figure is available in the online issue.)
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Figure 1: HF feeding reduces n-3 availability for resolution mediator synthesis. A: 8 weeks of HF feeding raised but fat-1 (F1) transgenesis restored the long-chain n-6:n-3 ratio in membrane phospholipids of muscle, liver, and epididymal adipose tissue. C, standard laboratory chow; AA, arachidonic acid (20:4 n-6); EPA, eicosapentaenoic acid (20:5 n-3); DPA, docosapentaenoic acid (22:5 n-3); DHA, docosahexaenoic acid (22:6 n-3). Data are mean ± SEM (n = 3). **P < 0.01 versus WTC; ***P < 0.001 versus WTC; †P < 0.05 versus WTHF; ††P < 0.01 versus WTHF. B: Comparison of n-3 docosanoid and eicosanoid biosynthetic pathways by LC-MS/MS in muscle, liver, and epididymal adipose tissue of HF-fed mice revealed that the docosanoid biosynthetic pathway has greater flux in metabolic tissues. Above left schematic diagram of docosanoid biosynthetic pathway showing the biosynthetic marker 17-HDoHE and PD1 (10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid [28]) as well as the immediate PD1 precursor 17-HpDoHE. At right, the eicosanoid pathway showing 18-HEPE and RvE1 (5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA [29]). ND indicates not detected. Data are mean ± SEM (n = 9–14). *P < 0.05, **P < 0.01, ***P < 0.001 versus 17-HDoHE. C: Representative LC-MS/MS spectra for 17-HDoHE, PD1, and 18-HEPE; retention times were 22.6, 18.2, and 20.6 min, respectively. D: Comparison of n-3 docosanoid and eicosanoid biosynthetic pathway activity by LC-MS/MS in muscle, liver, and epididymal adipose tissue of HF-fed wild-type and F1 mice reveals increased levels of docosanoid resolution mediator synthesis in muscle and adipose tissue of F1 mice compared with wild-type mice. Data are mean ± SEM (n = 6–10). *P < 0.05 versus WTHF. (A high-quality color representation of this figure is available in the online issue.)

Mentions: We first examined the effect of HF feeding on n-3 bioavailability in metabolic tissues. The HF diet mimicked Western diets in terms of n-3 content with an n-6:n-3 ratio of ∼18–1. After 8 weeks, HF-fed wild-type mice displayed an elevated long-chain n-6:n-3 ratio in skeletal muscle, liver, and adipose tissue membranes compared with their chow-fed counterparts (Fig. 1A). Importantly, transgenic expression of the fat-1 n-3 fatty acid desaturase that converts endogenous n-6 to n-3 fatty acids restored the membrane long-chain n-6:n-3 ratio of HF-fed fat-1 mice to levels comparable to chow-fed mice (Fig. 1A).


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.

White PJ, Arita M, Taguchi R, Kang JX, Marette A - Diabetes (2010)

HF feeding reduces n-3 availability for resolution mediator synthesis. A: 8 weeks of HF feeding raised but fat-1 (F1) transgenesis restored the long-chain n-6:n-3 ratio in membrane phospholipids of muscle, liver, and epididymal adipose tissue. C, standard laboratory chow; AA, arachidonic acid (20:4 n-6); EPA, eicosapentaenoic acid (20:5 n-3); DPA, docosapentaenoic acid (22:5 n-3); DHA, docosahexaenoic acid (22:6 n-3). Data are mean ± SEM (n = 3). **P < 0.01 versus WTC; ***P < 0.001 versus WTC; †P < 0.05 versus WTHF; ††P < 0.01 versus WTHF. B: Comparison of n-3 docosanoid and eicosanoid biosynthetic pathways by LC-MS/MS in muscle, liver, and epididymal adipose tissue of HF-fed mice revealed that the docosanoid biosynthetic pathway has greater flux in metabolic tissues. Above left schematic diagram of docosanoid biosynthetic pathway showing the biosynthetic marker 17-HDoHE and PD1 (10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid [28]) as well as the immediate PD1 precursor 17-HpDoHE. At right, the eicosanoid pathway showing 18-HEPE and RvE1 (5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA [29]). ND indicates not detected. Data are mean ± SEM (n = 9–14). *P < 0.05, **P < 0.01, ***P < 0.001 versus 17-HDoHE. C: Representative LC-MS/MS spectra for 17-HDoHE, PD1, and 18-HEPE; retention times were 22.6, 18.2, and 20.6 min, respectively. D: Comparison of n-3 docosanoid and eicosanoid biosynthetic pathway activity by LC-MS/MS in muscle, liver, and epididymal adipose tissue of HF-fed wild-type and F1 mice reveals increased levels of docosanoid resolution mediator synthesis in muscle and adipose tissue of F1 mice compared with wild-type mice. Data are mean ± SEM (n = 6–10). *P < 0.05 versus WTHF. (A high-quality color representation of this figure is available in the online issue.)
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Figure 1: HF feeding reduces n-3 availability for resolution mediator synthesis. A: 8 weeks of HF feeding raised but fat-1 (F1) transgenesis restored the long-chain n-6:n-3 ratio in membrane phospholipids of muscle, liver, and epididymal adipose tissue. C, standard laboratory chow; AA, arachidonic acid (20:4 n-6); EPA, eicosapentaenoic acid (20:5 n-3); DPA, docosapentaenoic acid (22:5 n-3); DHA, docosahexaenoic acid (22:6 n-3). Data are mean ± SEM (n = 3). **P < 0.01 versus WTC; ***P < 0.001 versus WTC; †P < 0.05 versus WTHF; ††P < 0.01 versus WTHF. B: Comparison of n-3 docosanoid and eicosanoid biosynthetic pathways by LC-MS/MS in muscle, liver, and epididymal adipose tissue of HF-fed mice revealed that the docosanoid biosynthetic pathway has greater flux in metabolic tissues. Above left schematic diagram of docosanoid biosynthetic pathway showing the biosynthetic marker 17-HDoHE and PD1 (10R,17S-dihydroxydocosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid [28]) as well as the immediate PD1 precursor 17-HpDoHE. At right, the eicosanoid pathway showing 18-HEPE and RvE1 (5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA [29]). ND indicates not detected. Data are mean ± SEM (n = 9–14). *P < 0.05, **P < 0.01, ***P < 0.001 versus 17-HDoHE. C: Representative LC-MS/MS spectra for 17-HDoHE, PD1, and 18-HEPE; retention times were 22.6, 18.2, and 20.6 min, respectively. D: Comparison of n-3 docosanoid and eicosanoid biosynthetic pathway activity by LC-MS/MS in muscle, liver, and epididymal adipose tissue of HF-fed wild-type and F1 mice reveals increased levels of docosanoid resolution mediator synthesis in muscle and adipose tissue of F1 mice compared with wild-type mice. Data are mean ± SEM (n = 6–10). *P < 0.05 versus WTHF. (A high-quality color representation of this figure is available in the online issue.)
Mentions: We first examined the effect of HF feeding on n-3 bioavailability in metabolic tissues. The HF diet mimicked Western diets in terms of n-3 content with an n-6:n-3 ratio of ∼18–1. After 8 weeks, HF-fed wild-type mice displayed an elevated long-chain n-6:n-3 ratio in skeletal muscle, liver, and adipose tissue membranes compared with their chow-fed counterparts (Fig. 1A). Importantly, transgenic expression of the fat-1 n-3 fatty acid desaturase that converts endogenous n-6 to n-3 fatty acids restored the membrane long-chain n-6:n-3 ratio of HF-fed fat-1 mice to levels comparable to chow-fed mice (Fig. 1A).

Bottom Line: The catabasis of inflammation is an active process directed by n-3 derived pro-resolving lipid mediators.Metabolic tissues were then harvested for biochemical analyses.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Faculty of Medicine, Cardiology axe, Quebec Heart and Lung Institute, CHUQ Research Centre, and INAF, Laval University, Quebec, Canada.

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.

Show MeSH
Related in: MedlinePlus