The inhibition of fat cell proliferation by n-3 fatty acids in dietary obese mice

Abstract

Background: Long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFA) of marine origin exert multiple beneficial effects on health. Our previous study in mice showed that reduction of adiposity by LC n-3 PUFA was associated with both, a shift in adipose tissue metabolism and a decrease in tissue cellularity. The aim of this study was to further characterize the effects of LC n-3 PUFA on fat cell proliferation and differentiation in obese mice.

Methods: A model of inducible and reversible lipoatrophy (aP2-Cre-ERT2 PPARγL2/L2 mice) was used, in which the death of mature adipocytes could be achieved by a selective ablation of peroxisome proliferator-activated receptor γ in response to i.p. injection of tamoxifen. Before the injection, obesity was induced in male mice by 8-week-feeding a corn oil-based high-fat diet (cHF) and, subsequently, mice were randomly assigned (day 0) to one of the following groups: (i) mice injected by corn-oil-vehicle only, i.e."control" mice, and fed cHF; (ii) mice injected by tamoxifen in corn oil, i.e. "mutant" mice, fed cHF; (iii) control mice fed cHF diet with15% of dietary lipids replaced by LC n-3 PUFA concentrate (cHF+F); and (iv) mutant mice fed cHF+F. Blood and tissue samples were collected at days 14 and 42.

Results: Mutant mice achieved a maximum weight loss within 10 days post-injection, followed by a compensatory body weight gain, which was significantly faster in the cHF as compared with the cHF+F mutant mice. Also in control mice, body weight gain was depressed in response to dietary LC n-3 PUFA. At day 42, body weights in all groups stabilized, with no significant differences in adipocyte size between the groups, although body weight and adiposity was lower in the cHF+F as compared with the cHF mice, with a stronger effect in the mutant than in control mice. Gene expression analysis documented depression of adipocyte maturation during the reconstitution of adipose tissue in the cHF+F mutant mice.

Conclusion: Dietary LC n-3 PUFA could reduce both hypertrophy and hyperplasia of fat cells in vivo. Results are in agreement with the involvement of fat cell turnover in control of adiposity.

Figure 1

Growth characteristics. After 8 weeks of high-fat (cHF) feeding, mice were randomly assigned to one of the following groups: (i) control mice, fed cHF (cHF PPARγ^ad+/+); (ii) mutant mice, fed cHF (cHF PPARγ^ad-/-); (iii) control mice, fed cHF enriched by LC n-3 PUFA (cHF+F PPARγ^ad+/+); and (iv) mutant mice, fed cHF+F (cHF+F PPARγ^ad-/-). Part of mice were killed at day 14, while the remaining mice were killed at day 42. A Body weights; B Frequency distribution of adipocyte cell surface area in epididymal fat at day 42. Data are means ± SE; n = 10.

Figure 2

Analysis of gene expression in epididymal fat. Transcript levels were measured using qRT-PCR in total RNA isolated from epididymal fat at day 14 or day 42. Scd-1, stearoyl-Coenzyme A desaturase 1; Cidec, cell death-inducing DFFA-like effector c; Pgc-1α, peroxisome proliferative activated receptor γ, coactivator 1 alpha; Pparα, peroxisome proliferator activated receptor α; Cox3, cytochrome c oxidase subunit III. Data are means ± SE; n = 10; a, b, c - significant differences compared to cHF PPARγ^ad+/+, cHF+F PPARγ^ad+/+, and cHF PPARγ^ad-/-, respectively.