Obesity‐induced insulin resistance and hepatic steatosis are alleviated by ω‐3 fatty acids: a role for resolvins and protectins

Abstract

Omega-3-polyunsaturated fatty acids (omega-3-PUFAs) have well-documented protective effects that are attributed not only to eicosanoid inhibition but also to the formation of novel biologically active lipid mediators (i.e., resolvins and protectins). In this study, we examined their effects on ob/ob mice, an obesity model of insulin resistance and fatty liver disease. Dietary intake of omega-3-PUFAs had insulin-sensitizing actions in adipose tissue and liver and improved insulin tolerance in obese mice. Genes involved in insulin sensitivity (PPARgamma), glucose transport (GLUT-2/GLUT-4), and insulin receptor signaling (IRS-1/IRS-2) were up-regulated by omega-3-PUFAs. Moreover, omega-3-PUFAs increased adiponectin, an anti-inflammatory and insulin-sensitizing adipokine, and induced AMPK phosphorylation, a fuel-sensing enzyme and a gatekeeper of the energy balance. Concomitantly, hepatic steatosis was alleviated by omega-3-PUFAs. A lipidomic analysis with liquid chromatography/mass spectrometry/mass spectrometry revealed that omega-3-PUFAs inhibited the formation of omega-6-PUFA-derived eicosanoids, while triggering the formation of omega-3-PUFA-derived resolvins and protectins. Moreover, representative members of these lipid mediators, namely resolvin E1 and protectin D1, mimicked the insulin-sensitizing and antisteatotic effects of omega-3-PUFAs and induced adiponectin expression to a similar extent that of rosiglitazone, a member of the thiazolidinedione family of antidiabetic drugs. Taken together, these findings uncover beneficial actions of omega-3-PUFAs and their bioactive lipid autacoids in preventing obesity-induced insulin resistance and hepatic steatosis.

Synergistic induction of lipid catabolism and anti-inflammatory lipids in white fat of dietary obese mice in response to calorie restriction and n-3 fatty acids

“…Metabolic syndrome is linked to inflammatory changes in both WAT and liver [1]. In this study, in accordance with the previous findings [17,18,21], dietary LC n-3 PUFA supplementation resulted in the inhibition of formation of various LC n-6 PUFA-derived pro-inflammatory eicosanoids in both tissues as well as in the induction of the antiinflammatory molecules. In WAT, in contrast to the liver, the levels of EPA, DHA, AA and their active metabolites, including the anti-inflammatory molecules PD1 and prostaglandin 15d-PGJ 2, were increased in a synergistic manner by the combination treatment (Fig.…”

“…The anti-inflammatory effects of LC n-3 PUFA probably depend on the formation of their active metabolites. These lipid mediators originate from either targeted enzymatic synthesis, such as resolvins and protectins [17,18], or from non-enzymatic oxidation reactions [19,20]. They can act as ligands for surface receptors or can interact with signalling proteins including the transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor κ light-chain enhancer of activated B cells (NF-κB) [19].…”

“…They can act as ligands for surface receptors or can interact with signalling proteins including the transcription factors peroxisome proliferator-activated receptor γ (PPARγ) and nuclear factor κ light-chain enhancer of activated B cells (NF-κB) [19]. Notably, resolvins and protectins mediate the antiinflammatory and protective actions of LC n-3 PUFA in obesity-induced insulin resistance and hepatic steatosis [17,21]. As LC n-3 PUFA and LC n-6 PUFA compete for common enzymatic pathways, a relatively small increase in the LC n-3 PUFA intake usually slows down synthesis of pro-inflammatory metabolites derived from arachidonic acid (AA; 20:4 n-6) [17,18].…”

“…Notably, resolvins and protectins mediate the antiinflammatory and protective actions of LC n-3 PUFA in obesity-induced insulin resistance and hepatic steatosis [17,21]. As LC n-3 PUFA and LC n-6 PUFA compete for common enzymatic pathways, a relatively small increase in the LC n-3 PUFA intake usually slows down synthesis of pro-inflammatory metabolites derived from arachidonic acid (AA; 20:4 n-6) [17,18]. Given the complexity of factors contributing to the development of metabolic syndrome, its prevention and treatment requires strategies combining several approaches.…”

n-3 PUFA: bioavailability and modulation of adipose tissue function

“…This metabolic switch may reduce the accumulation of toxic fatty acid derivatives, while protecting the insulin signalling in liver and muscle (9,13,24,30,35) . Part of the metabolic effects of n-3 LC PUFA in the liver (36) , and possibly also in other tissues (24,37) (also, see later), is mediated by the stimulation of AMP-activated protein kinase (AMPK), a metabolic sensor controlling intracellular metabolic fluxes, i.e. the partitioning between lipid oxidation and lipogenesis (for review, see Flachs et al (23) and Carling (38) ).…”