Inhibition of inflammatory response in transgenic fat-1 mice on a calorie-restricted diet

https://doi.org/10.1016/j.bbrc.2006.08.093Get rights and content

Abstract

Both n  3 fatty acids (n  3 FA) and calorie-restriction (CR) exert anti-inflammatory effects in animal models of autoimmunity and inflammation. In the present study we investigated the synergistic anti-inflammatory effects of n  3 FA and CR on LPS-mediated inflammatory responses using fat-1 transgenic mice that generate n  3 FA endogenously. Wild-type (WT) and fat-1 mice were maintained on ad libitum (AL) or CR (40% less than AL) diet for 5 mo; splenocytes were cultured in vitro with/without LPS. Our results show: (i) no difference in body weights between WT and fat-1 mice on AL or CR diets, (ii) lower n  6/n  3 FA ratio in splenocytes from fat-1 mice on both AL and CR diets, (iii) significant reduction in NF-κB (p65/p50) and AP-1 (c-Fos/c-Jun) DNA-binding activities in splenocytes from fat-1/CR mice following LPS treatment, and (iv) significant reduction in κB- and AP-1-responsive IL-6 and TNF-α secretion following LPS treatment in splenocytes from fat-1/CR mice. The inhibition of LPS-mediated effects was more pronounced in fat-1/CR mice when compared to fat-1/AL or WT/CR mice. These data show that transgenic expression of fat-1 results in decreased pro-inflammatory n  6 FA, and demonstrate for the first time that splenocytes from fat-1 mice on CR diet exhibit reduced pro-inflammatory response when challenged with LPS. These results suggest that n  3 lipids with moderate CR may confer protection in autoimmune and inflammatory diseases.

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Materials and methods

Animals and experimental diets. Heterozygous fat-1 mice on C57BL/6 background [24] were previously described. These animals show no phenotypic changes. Fat-1 heterozygous and the non-transgenic litter mate controls were used in the study. Presence of fat-1 gene was confirmed by genotyping and fatty acid composition of tails by gas chromatography (GC). Age- and weight-matched mice were housed in a laboratory animal care facility in cages (3–4 mice/cage) and fed semi-purified AIN-93 M diets

Body weight

Body weights increased gradually in WT/AL and fat-1/AL mice but there was no difference between the 2 groups (p = 0.38). As expected, CR reduced body weight in both WT and fat-1 mice as compared to AL mice, but the difference were not statistically different between the 2 groups (p = 0.18) (Fig. 1).

Fatty acid composition of splenocytes

We performed GC to determine the effect of fat-1 transgene on fatty acid composition of splenocytes. Our results showed decrease in n  6/n  3 FA ratio in fat-1/AL and fat-1/CR mice as compared to WT/AL

Discussion

This is the first study to demonstrate the inhibition of LPS-induced inflammatory response in fat-1 transgenic mice on CR diet. There was significant inhibition of NF-κB p65/p50 activity, AP-1 c-Fos/c-Jun activity, and pro-inflammatory cytokine expression, ex vivo, in fat-1/CR mice. These findings suggest that n  3 FA and CR, in combination, may prevent or delay the progression of inflammatory diseases. We previously demonstrated the anti-inflammatory and life-prolonging effects of n  3 FA in

Acknowledgments

We thank Kazi Nishu for her assistance in diet preparation and animal maintenance. This work was supported by the National Institutes of Health Grants AG023648 and AG027562 (G.F.), by the Research Service of the Department of Veterans Affairs (B.C.), and the American Cancer Society Grant RSG-03-140-01-CNE (J.X.K).

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