EPA and DHA elicit distinct transcriptional responses to high-fat feeding in skeletal muscle and liver

Abstract

Omega-3 polyunsaturated fatty acids ( n-3 PUFAs) exert numerous beneficial biological effects and attenuate diet-induced insulin resistance in rodent models. In the present study, the independent, tissue-specific effects of two nutritionally relevant n-3 PUFAs, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), were characterized in the context of a high-fat diet (HFD). EPA and DHA supplementation (3.2% of total fat) in 6-mo-old male C57BL/6 mice fed an HFD (60% fat) partially mitigated reductions in insulin sensitivity. At 5 wk, the area above the curve below baseline glucose following an intraperitoneal insulin tolerance test was 54.5% lower in HFD than control, whereas HFD + EPA and HFD + DHA showed 27.6% and 17.1% reductions, respectively. At 10 wk, HFD increased mitochondrial oxidative capacity supported by lipid and carbohydrate-based substrates in both liver and skeletal muscle ( P < 0.05), with little effect of EPA or DHA supplementation. Whole genome transcriptomic analyses revealed HFD-induced transcriptional changes indicative of inflammation and fibrosis in both liver and muscle. Gene set enrichment analyses indicated a downregulation of transcripts associated with extracellular matrix in muscle (family-wise error rate P < 0.01) and liver ( P = 0.04) and in transcripts associated with inflammation in muscle ( P = 0.03) in HFD + DHA compared with HFD alone. In contrast, EPA appeared to potentiate some proinflammatory effects of the HFD. In the skeletal muscle, DHA increased the expression of stress-responsive genes, whereas EPA upregulated the expression of transcripts related to cell cycle. Therefore, although both EPA and DHA supplementation during HFD partially preserve insulin signaling, they modulate distinct processes, highlighting their unique biological effects in the context of obesity.

Are marine n-3 fatty acids protective towards insulin resistance? From cell to human

“…Marine n -3 also decrease inflammation in muscle of HFD-fed rats (22 % fish oil inside a 40 % fat diet) (58) , the effect being observed with DHA but not with EPA (3⋅2 % of total fat) (60) . DHA (30 μ m ) prevented IR in C2C12 myotubes exposed to palmitate (500 μ m ) by decreasing protein kinase C-θ activation and restoring cellular acylcarnitine profile, insulin-dependent Akt phosphorylation and glucose uptake (61) .…”

Co-Administration of Propionate or Protocatechuic Acid Does Not Affect DHA-Specific Transcriptional Effects on Lipid Metabolism in Cultured Hepatic Cells

“…With unique chemical structures and three-dimensional configurations, n-3 LC-PUFAs influence multiple relevant molecular pathways, which individually or in sum might contribute to the observed effects on physiological risk factors and clinical events. A lingering issue in this field is that most studies of n-3 LC-PUFAs involve fish oil or mixtures of EPA and DHA without considering that each fatty acid could have distinct biological effects and tissue specific effects [ 44 ]. The present study was conducted to further characterize the independent, specific effect of DHA on the transcriptome of liver cells.…”

Targeting Energy Expenditure—Drugs for Obesity Treatment

“…These compounds show the attenuation of high-fat diet-induced insulin resistance and potent anti-inflammatory effects, which inhibit macrophage infiltration into adipose tissue. DHA (doconexent) and EPA (icosapent) reduce insulin resistance [ 19 ].…”

“…n-3 PUFAs trigger distinct transcriptional changes in the liver and skeletal muscle when supplemented. These transcriptional patterns are attenuated by DHA but amplified by EPA, which suggests that these fatty acids are nutritionally essential and have distinct biological effects [ 19 , 22 ]. n-3 PUFAs increase energy expenditure in mice by activating brown and beige adipocyte UCP1-mediated non-shivering thermogenesis [ 23 ].…”