Comparing Transgenic Production to Supplementation of ω-3 PUFA Reveals Distinct But Overlapping Mechanisms Underlying Protection Against Metabolic and Hepatic Disorders

Abstract

We investigated how endogenous ω-3 PUFA production compared to supplementation could improve obesity-related metabolic dysfunction. Fat-1 transgenic mice, able to endogenously convert exogenous ω-6 to ω-3 PUFA, and their wild-type littermates were fed a high-fat diet and daily gavaged with either ω-3 or ω-6 PUFA-rich oil for 12 weeks. The endogenous production of ω-3 PUFA improved glucose intolerance and insulin resistance but did not affect hepatic steatosis. Conversely, ω-3 PUFA supplementation fully prevented hepatic steatosis but failed to improve insulin resistance. Both models increased levels of ω-3 PUFA-containing 2–monoacylglycerol and N-acylethanolamine congeners, and reduced levels of ω-6 PUFA-derived endocannabinoids, in the liver and gastrocnemius muscle, with different impact at molecular species levels, and supplementation of ω-3 PUFAs being more efficacious. Reduced hepatic lipid accumulation was shown to be associated with the endocannabinoidome metabolites EPEA and DHEA, which was causally demonstrated by lower lipid accumulation in oleic acid-treated hepatic cells treated with these metabolites. While both genetic and supplementation models induced a significant fecal enrichment of the beneficial Allobaculum genus, mice gavaged with ω-3 PUFA also displayed additional changes in the gut microbiota functions with significant reduction of fecal levels of the pro-inflammatory molecules lipopolysaccharide and flagellin. By employing multiple factor analysis, we were able to identify that the metabolic improvements induced by ω-3 PUFA were accompanied by a reduced production of the pro-inflammatory cytokine TNFα, and that ω-3 PUFA supplementation had a stronger effect on improving the hepatic fatty acid profile than endogenous ω-3 PUFA. In conclusion, while endogenous ω-3 PUFA production preferably improves glucose tolerance and insulin resistance, oral ω-3 PUFA intake appears to be required to elicit selective changes in hepatic endocannabinoidome signaling that are essential to alleviate high-fat diet-induced hepatic steatosis.

Do Endogenously Produced and Dietary ω-3 Fatty Acids Act Differently?

“…Fat-1 mice are described to have a different gut microbiota from wild-type mice, 10 and this might relate to altered fatty acid composition of the gut epithelium and/or to effects of systemic ω-3 PUFAs on the gut-associated immune and inflammatory systems. If this mechanism is important in fat-1 mice, it might be that the lower levels of ω-3 PUFAs achieved in the fat-1 mice studied by Daniel et al 7 are too low to have a strong influence on the intestinal tract ecosystem.…”

“…Daniel et al 7 use wild-type C57Bl/6 mice and fat-1 mice. The latter are transgenic mice expressing the fat-1 gene from Caenorhabditis elegans , which encodes an enzyme with delta-15 desaturase activity, and so able to convert ω-6 into ω-3 PUFAs.…”

“…These findings are consistent with much human research on the longer-chain ω-3 PUFAs like EPA and DHA. In their study, Daniel et al 7 fed both types of mouse diets low or high in fat (10% or 55% energy from fat), which provided modest amounts of LA. These experiments allowed the response of wild-type and fat-1 mice to high-fat feeding to be compared.…”

“…Dietary ω-3 PUFAs enter the body in chylomicrons and are cleared, in part, by adipose tissue, where they are stored, but where they also have biological effects. In this regard, Daniel et al 7 show that visceral adipose tissue weight and the plasma concentration of the adipose tissue-derived hormone leptin are lower in wild-type mice fed fish oil than in the comparator group, suggesting that dietary ω-3 PUFAs have direct effects on adipose tissue. ω-3 PUFAs are subsequently delivered to the liver in remnant particles and in a nonesterified form.…”

The Gut Microbiome–Endocannabinoidome Axis: A New Way of Controlling Metabolism, Inflammation, and Behavior

“…These usually lead to the prevalence of “beneficial” eCBome mediators and gμBiome taxa. 2 , 3 While it is now clear that the effects of dietary fatty acids in either case can be direct as well as rapid and reversible, 2 , 3 it is still not known to what extent such actions can also be the indirect consequence of effects of the the gμBiome on the eCBome and vice versa .…”