Abstract
The present study evaluates the effect of flaxseed oil (FXO) supplementation on adipose tissue macrophages (ATM’s), E and D series resolvin (Rv) levels and adipose tissue inflammation. Male C57BL/6J mice were divided into five groups (n = 5): lean group (given standard chow diet), HFD group given high fat diet (approx. 18 weeks) till they developed insulin resistance and 4, 8 or 16 mg/kg group (HFD group later orally supplemented with 4, 8 or 16 mg/kg body weight flaxseed oil) for 4 weeks.The present study showed that FXO supplementation led to enhanced DHA, EPA, RvE1-E2, RvD2, RvD5- D6, IL-4, IL-10 and arginase 1 levels in ATMs together with altered immune cell infiltration and reduced NF-κB expression. The FXO supplementation suppresses immune cell infiltration into adipose tissue and alters adipose tissue macrophage phenotype towards the anti-inflammatory state via enhancement of E and D series resolvins, arginase 1 expression and anti-inflammatory cytokines level (IL-4 and IL-10.) leading to amelioration of insulin resistance in flaxseed oil supplemented HFD mice.
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Key Points
The altered resolution of inflammation under conditions of obesity and insulin resistance may be modulated by therapeutic interventions or modification in diet/ lifestyle that lead to macrophage switching. Flaxseed oil is a rich source of alpha-linolenic acid (ALA), known ligands for peroxisome proliferator-activated receptors (PPARs) especially PPAR-α which are regulators of cell metabolism.
In the present study, the therapeutic effect of flaxseed oil supplementation on the obese insulin-resistant model was assessed. FXO supplementation high-fat diet fed obese insulin-resistant mice increases EPA, DHA, resolvin RvE1, RvE2, RvD2, RvD6 levels, inhibits macrophage infiltration into the adipose tissue and reduces pro-inflammatory cytokines production by ATMs leading to improved insulin sensitivity through adipose tissue remodelling. FXO treatment improved insulin sensitivity in obese mice.
The supplementation with dietary ALA might be compensating for the reduced activity of liver enzymes to synthesize EPA and DHA that in turn improves metabolism and in turn resolves adipose tissue inflammation.
Further, the histopathological analysis of H & E stained adipose tissue that showed markedly immune cells infiltrated adipose tissue from HFD mice in comparison to lean group and reduction in immune cell population upon FXO supplementation. Resolvins are known to be potentially involved in reversing inflammatory status through damping the production of pro-inflammatory cytokines (TNF-α and IFN-γ), modulation of inflammatory pathways and inhibition of chemokine formation. In this study, we found that FXO treatment results in inhibition of pro-inflammatory cytokines (IL-2, TNF-α and IFN-γ) production and upregulation of anti-inflammatory cytokines (IL-4, IL-10). In conclusion, the findings indicate that the flaxseed oil provides the raw material i.e. EPA and DHA for the synthesis of E and D series resolvins by adipose tissue macrophages and aid in adipose tissue remodeling via regulating inflammatory status (pro- or anti-) of adipose tissue macrophages thereby protecting against obesity-induced adipose tissue inflammation and insulin resistance.