Differential effects of EPA, DPA and DHA on cardio-metabolic risk factors in high-fat diet fed mice

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Highlights

  • The effects of the three n-3 PUFAs (EPA, DPA and DHA) on serum biochemical parameters in mice with cardio-metabolic syndrome were systematically investigated.

  • Supplementation with DPA was shown to be more superior to decrease blood glucose and improve insulin resistance compared with EPA and DHA. DPA and DHA groups significantly trigged adiponectin secretion, and protected against liver injury, compared with the EPA group.

  • The protective mechanisms of n-3 PUFAs supplementation were attributed to down-regulating TLR-4/NF-κB signaling pathway and decreasing lipogenesis in the liver.

Abstract

The aim of the present study was to assess and compare the effects of eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) supplementation on lipid metabolism in 4 month-old male C57BL/6J mice fed a high-fat diet. The high-fat fed mice showed evidence of fatty liver, obesity and insulin resistance after being on the high-fat diet for 6 weeks compared with the control low-fat diet fed mice. Supplementation of the high-fat diet with either EPA, DPA or DHA prevented the fatty liver, prevented high serum cholesterol and serum glucose and prevented high liver cholesterol levels. DPA (but not EPA or DHA) was associated with a significantly improved homeostasis model assessment of insulin resistance (HOMA-IR) compared with the high-fat fed mice. Supplementation with DPA and DHA both prevented the decreased serum adiponectin levels, compared with EPA and the high-fat diet. In addition, supplementation with DPA and DHA both prevented the increased serum alanine aminotransferase (ALT) levels compared with EPA and the high-fat group, which can be attributed to down-regulation of TLR-4/NF-κB signaling pathway and decreasing lipogenesis in the liver. Therefore, DPA and DHA seem to exert similar effects in cardio-metabolic protection against the high-fat diet and these effects seem to be different to those of EPA.

Introduction

Cardio-metabolic disorder, formerly called metabolic syndrome, is widely defined as the combination of risk factors responsible for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) [1]. With changes in lifestyles, the prevalence of metabolic syndrome is predicted to exceed 50% in the U.S population over 50 years of age, owing to obesity [2]. Interactions of genetics and environmental factors are responsible for the initiation and development of metabolic syndrome. Regarding environmental factors, a dietary pattern of excess calories, rich in fat and simple carbohydrates contributes to the development of obesity. Excessive caloric intake increases adipose tissue and fat storage, causing increases in plasma free fatty acids (FFA) and accumulation of triglyceride(TAG) in liver and muscle which eventually leads to decreased capacity of glucose and lipid metabolism in peripheral tissues in response to insulin [3], [4], resulting in insulin resistance and metabolic syndrome. Increased adipose tissue also leads to increases in cytokine production causing inflammation which further exacerbates the insulin resistance. There is a substantial literature which has revealed that supplementation with long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) is associated with improving glucose and lipid metabolism in subjects with metabolic syndrome [2], [5], [6]. Long-chain n-3 PUFAs, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) have been widely researched, and shown to have cardio-protective effect by the anti-inflammatory effects of their meditators, reductions in plasma TAG levels, reducing platelet aggregation, lowering blood pressure [7], and activating peroxisome proliferator activated receptors (PPARs) and G protein-coupled receptor 120 (GPR120) signaling pathways [2], [8], [9], [10].

Docosapentaenoic acid (DPA) n-3 is the predominant n-3 PUFAs in beef, goat and lamb flesh and certain marine species such as abalone and menhaden [11]. There have been few studies on the biological effects of DPA owing to the difficulty of its purification from marine oils [12], [13]. Recent reviews have summarized the possible role of DPA intake related to cardiovascular health benefits, mental health, and cancers [14], [15]. There is only one human trial to date with pure DPA showing differential effects compared with pure EPA, in terms of chylomicronemia [16], incorporation into red cell membranes [17] and production of lipid mediators [18]. Current evidence suggests EPA, DPA and DHA may have independent and shared effects for health benefits [5], [15].

Although EPA and DHA have been studied in relation to prevention or reversal of metabolic syndrome in rodent models [19], [20], [21], there have been no published studies in this area on DPA. Therefore, the objective of the present study was to evaluate and compare the three long-chain n-3 PUFAs on serum biochemical parameters and inflammatory biomarkers and molecular mechanisms related to glucose and lipid metabolism in mice with cardio-metabolic risk factors induced by a high-fat diet.

Section snippets

Fatty acids

EPA (98%; W/W), DPA (72%; W/W), and DHA (97%; W/W), as ethyl esters, were kindly provided by Bizen Chemical Co., LTD (Okayama, Japan). The PUFAs were diluted in olive oil for administration to the mice. Thirteen grams of each of EPA, DPA and DHA were mixed into 30 g of olive oil in 50 ml tubes. Then the solutions were blended and sub-packaged into 1.5 ml tubes sealed with nitrogen and stored at − 20 °C for later use.

Animals

Male C57BL/6J mice aged 2 months were purchased from Slacom Co., LTD (Shanghai,

Bodyweight and caloric intake

The animals on the high-fat diets showed significantly increased cumulative weight gain compared with the control group after 6 weeks of intervention (Fig. 1). In addition, although not significant, the cumulative weight gain was decreased by 12.3%, 11.0% and 11.1% in the HF-EPA, -DPA and -DHA groups, respectively, compared with the HF-OO group. The low-fat control group had a significantly higher food intake per day compared with the other groups (Fig. 2A). Mice given DHA had a significantly

Discussion

Obesity is defined by excess body fat, and is generally associated with a low-grade and chronic inflammatory state [27], [28], [29], [30]. Mounting evidence has revealed that the accumulation of white adipose tissue is associated with elevation of macrophage infiltration of the adipose tissue, circulating free fatty acids and cytokines such as TNF-α, which would trigger TLR-4 signaling pathways and inhibit insulin signaling pathways [28], [31], [32], leading to various kinds of cardio-metabolic

Acknowledgement

We thank Bizen Chemical Co., LTD for the generous provision of the pure supplements. This study was funded by the National Basic Research Program of China (973 Program: 2015CB553604); by National Natural Science Foundation of China (NSFC: 81273054); and by the Ph.D. Programs Foundation of Ministry of Education of China (20120101110107). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Author contribution

X.G, AJS and D.L conceived the

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