Limits...
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.

Show MeSH

Related in: MedlinePlus

Transgenic restoration of long-chain n-3 PUFA protects against obesity-linked insulin resistance and glucose intolerance. A: HF-diet–induced elevation of fasting plasma insulin was prevented by transgenic restoration of n-3 derived resolution mediators (n = 4–9). B: Glycemic excursion from 1.5 U/kg i.p. ITT was normalized in HF-fed F1 mice (n = 8–12). C: Glycemic excursion expressed as percent basal glycemia. D: Percent basal glycemia at T = 15 min after insulin injection. E: Glycemic excursion from 1g/kg i.p. GTT expressed as percent basal glycemia (n = 7–11), and (F) area under the curve from GTT show that HF-fed F1 mice are partially protected from glucose intolerance. G: HF-fed F1 mice develop similar obesity to wild-type mice. Weight gain (n = 16–20). H: Epididymal fat pad weight (n = 9–14). I: Liver weight (n = 9–14). J: Representative hematoxylin and eosin stained liver sections showing similar accumulation of fat vesicles in both WTHF and F1HF mice. All data are mean ± SEM, ND not detected, *P < 0.05, **P < 0.01, ***P < 0.001 versus respective chow-fed control; †P < 0.05 versus WTHF. (A high-quality color representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2992767&req=5

Figure 3: Transgenic restoration of long-chain n-3 PUFA protects against obesity-linked insulin resistance and glucose intolerance. A: HF-diet–induced elevation of fasting plasma insulin was prevented by transgenic restoration of n-3 derived resolution mediators (n = 4–9). B: Glycemic excursion from 1.5 U/kg i.p. ITT was normalized in HF-fed F1 mice (n = 8–12). C: Glycemic excursion expressed as percent basal glycemia. D: Percent basal glycemia at T = 15 min after insulin injection. E: Glycemic excursion from 1g/kg i.p. GTT expressed as percent basal glycemia (n = 7–11), and (F) area under the curve from GTT show that HF-fed F1 mice are partially protected from glucose intolerance. G: HF-fed F1 mice develop similar obesity to wild-type mice. Weight gain (n = 16–20). H: Epididymal fat pad weight (n = 9–14). I: Liver weight (n = 9–14). J: Representative hematoxylin and eosin stained liver sections showing similar accumulation of fat vesicles in both WTHF and F1HF mice. All data are mean ± SEM, ND not detected, *P < 0.05, **P < 0.01, ***P < 0.001 versus respective chow-fed control; †P < 0.05 versus WTHF. (A high-quality color representation of this figure is available in the online issue.)

Mentions: We next characterized whole-body insulin sensitivity to determine whether transgenic restoration of n-3 also prevents the development of obesity-linked insulin resistance. Insulin sensitivity was markedly reduced in HF-fed wild-type mice, as illustrated by elevated fasting insulin levels and diminished glucose excursion during the ITT (Fig. 3A–D). Conversely, fat-1 mice were protected from HF-diet-induced insulin resistance because both fasting insulin values and ITT curves were similar to those observed for chow-fed mice.


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)

Transgenic restoration of long-chain n-3 PUFA protects against obesity-linked insulin resistance and glucose intolerance. A: HF-diet–induced elevation of fasting plasma insulin was prevented by transgenic restoration of n-3 derived resolution mediators (n = 4–9). B: Glycemic excursion from 1.5 U/kg i.p. ITT was normalized in HF-fed F1 mice (n = 8–12). C: Glycemic excursion expressed as percent basal glycemia. D: Percent basal glycemia at T = 15 min after insulin injection. E: Glycemic excursion from 1g/kg i.p. GTT expressed as percent basal glycemia (n = 7–11), and (F) area under the curve from GTT show that HF-fed F1 mice are partially protected from glucose intolerance. G: HF-fed F1 mice develop similar obesity to wild-type mice. Weight gain (n = 16–20). H: Epididymal fat pad weight (n = 9–14). I: Liver weight (n = 9–14). J: Representative hematoxylin and eosin stained liver sections showing similar accumulation of fat vesicles in both WTHF and F1HF mice. All data are mean ± SEM, ND not detected, *P < 0.05, **P < 0.01, ***P < 0.001 versus respective chow-fed control; †P < 0.05 versus WTHF. (A high-quality color representation of this figure is available in the online issue.)
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2992767&req=5

Figure 3: Transgenic restoration of long-chain n-3 PUFA protects against obesity-linked insulin resistance and glucose intolerance. A: HF-diet–induced elevation of fasting plasma insulin was prevented by transgenic restoration of n-3 derived resolution mediators (n = 4–9). B: Glycemic excursion from 1.5 U/kg i.p. ITT was normalized in HF-fed F1 mice (n = 8–12). C: Glycemic excursion expressed as percent basal glycemia. D: Percent basal glycemia at T = 15 min after insulin injection. E: Glycemic excursion from 1g/kg i.p. GTT expressed as percent basal glycemia (n = 7–11), and (F) area under the curve from GTT show that HF-fed F1 mice are partially protected from glucose intolerance. G: HF-fed F1 mice develop similar obesity to wild-type mice. Weight gain (n = 16–20). H: Epididymal fat pad weight (n = 9–14). I: Liver weight (n = 9–14). J: Representative hematoxylin and eosin stained liver sections showing similar accumulation of fat vesicles in both WTHF and F1HF mice. All data are mean ± SEM, ND not detected, *P < 0.05, **P < 0.01, ***P < 0.001 versus respective chow-fed control; †P < 0.05 versus WTHF. (A high-quality color representation of this figure is available in the online issue.)
Mentions: We next characterized whole-body insulin sensitivity to determine whether transgenic restoration of n-3 also prevents the development of obesity-linked insulin resistance. Insulin sensitivity was markedly reduced in HF-fed wild-type mice, as illustrated by elevated fasting insulin levels and diminished glucose excursion during the ITT (Fig. 3A–D). Conversely, fat-1 mice were protected from HF-diet-induced insulin resistance because both fasting insulin values and ITT curves were similar to those observed for chow-fed mice.

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