Omega-3 weekly is more bio-available than daily (rat study) – July 2015

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What Is the Most Effective Way of Increasing the Bioavailability of Dietary Long Chain Omega-3 Fatty Acids—Daily vs. Weekly Administration of Fish Oil?

Nutrients 2015, 7(7), 5628-5645; doi:10.3390/nu7075241
Samaneh Ghasemifard 1,† , Andrew J. Sinclair 1,† , Gunveen Kaur 2 ,Paul Lewandowski 1 and Giovanni M. Turchini 3,*

The recommendations on the intake of long chain omega-3 polyunsaturated fatty acids (n-3 LC-PUFA) vary from eating oily fish (“once to twice per week”) to consuming specified daily amounts of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (“250–500 mg per day”). It is not known if there is a difference in the uptake/bioavailability between regular daily consumption of supplementsvs. consuming fish once or twice per week. In this study, the bioavailability of a daily dose of n-3 LC-PUFA (Constant treatment), representing supplements, vs. a large weekly dose of n-3 LC-PUFA (Spike treatment), representing consuming once or twice per week, was assessed. Six-week old healthy male Sprague-Dawley rats were fed either a Constant treatment, a Spike treatment or Control treatment (no n-3 LC-PUFA), for six weeks. The whole body, tissues and faeces were analysed for fatty acid content. The results showed that the major metabolic fate of the n-3 LC-PUFA (EPA+docosapentaenoic acid (DPA) + DHA) was towards catabolism (β-oxidation) accounting for over 70% of total dietary intake, whereas deposition accounted less than 25% of total dietary intake. It was found that significantly more n-3 LC-PUFA were β-oxidised when originating from the Constant treatment (84% of dose), compared with the Spike treatment (75% of dose). Conversely, it was found that significantly more n-3 LC-PUFA were deposited when originating from the Spike treatment (23% of dose), than from the Constant treatment (15% of dose). These unexpected findings show that a large dose of n-3 LC-PUFA once per week is more effective in increasing whole body n-3 LC-PUFA content in rats compared with a smaller dose delivered daily.
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Discussion (extracted from PDF)

The present study sought to examine the whole body bioavailability and efficiency (as n-3 LC-PUFA metabolic fate) of the same overall dose of n-3 LC-PUFA, provided from the same source (fish oil), at the same overall weekly dose, but at different frequencies: daily vs. weekly. It was found that the growth of the animals was not different between treatments and no mortalities were recorded amongst the three experimental treatments (Constant, Spike and Control). There were significant but small differences in the excretion of the n-3 LC-PUFA between the Spike and Constant treatment groups, which are unlikely to be nutritionally relevant.

The results obtained by simply comparing tissue FA concentrations (mg/g tissue) were interesting, but they are admittedly of limited value towards achieving a better understanding of n-3 LC-PUFA “bioavailability”. While the dietary intake of n-3 LC-PUFA provided by the two diets were similar, but not identical, there were some differences between treatments that might be independent of the difference in dietary intake. For example, the DPA concentration in liver and muscle was significantly greater in the Spike treatment than in the Constant treatment, despite the dietary DPA intake being significantly greater for the Constant treatment. This has no obvious explanation, but reveals that metabolic processing of dietary n-3 LC-PUFA is more complex than simply looking at dietary intake values or tissue levels.

A much greater and more accurate understanding of the actual metabolic fate of n-3 LC-PUFA provided by different oils can be achieved by observing the results of the Whole Body Fatty Acid Balance Method, which takes into account, and thus balances out, any differences in dietary intake.

This data showed that the major metabolic fate of the n-3 LC-PUFA (EPA + DPA + DHA) was towards catabolism (3-oxidation) accounting for over 70% of total dietary intake, whereas deposition accounted less than 25% of total dietary intake. It was found that significantly more n-3 LC-PUFA were 3-oxidised when originating from the Constant treatment (84% of dose), compared with the Spike treatment (75% of dose).
Conversely, it was found that significantly more n-3 LC-PUFA were deposited when originating from the Spike treatment (23% of dose), than from the Constant treatment (15% of dose). This result suggests that the n-3 LC-PUFA provided by the Spike treatment were more deposited (bioavailable), compared with those provided by the Constant treatment.

The differences in |3-oxidation and deposition were not the same for each of EPA, DPA and DHA for either the Spike or Constant treatment. That is, EPA was more extensively (3-oxidised than DPA and DHA on both treatments, but the differences between the 20 carbon and the 22 carbon PUFA were accentuated in the Spike treatment. In the case of (3-oxidation, the Constant/Spike ratios were 1.7 for DPA and 1.4 for DHA, but only 1.0 for EPA. In terms of deposition, the Constant/Spike ratios were 0.5 for DPA, 0.6 for DHA, and 0.7 for EPA. This suggests that EPA is preferentially directed towards 3-oxidation almost independent of whether the EPA is provided daily or once per week. This is consistent with data showing high affinity of EPA to catabolism (3-oxidation) in animal models [23]. It has been reported using Wistar rats that EPA-CoA was a good substrate for mitochondrial carnitine acyl-transferase-I and DHA was a poor substrate for both mitochondrial and peroxisomal 3-oxidation, which could explain the high rate of (3-oxidation for EPA [23].

In contrast to EPA, it would appear that DHA and DPA are somewhat spared from (3-oxidation when consumed, as observed previously [24] but especially when a large dose of dietary n-3 LC-PUFA is provided weekly. This is consistent with the finding of Kaur et al. [24] in rodents who showed, using radiolabelled EPA, DPA and DHA in rats, that six hours after dosing 19% of the EPA was |3-oxidized and expired as CO2 compared with 5% in case of DPA and 7% of DHA. However, these data do not shed any light on why providing a bolus dose of n-3 LC-PUFA leads to a greater partitioning of DPA and DHA towards deposition. With the Spike treatment, it is therefore possible to speculate that this “flood” of n-3 LC-PUFA could have saturated the capacity of the mitochondria to (3-oxidise any extra DPA and DHA, resulting in a greater retention and deposition of these fatty acids in tissues.

To our knowledge, this is the first study to compare the whole body bioavailability of n-3 LC-PUFA in rats fed a constant daily dose vs. a larger and less frequent dose of the same dietary source of n-3 LC-PUFA. From the two available human studies comparing a weekly dose of n-3 LC-PUFA with daily dose, only one study used the same source of n-3 LC-PUFA (capsules not fish meal) [12]. Both studies used blood levels (plasma, platelets or mononuclear cells) as a proxy for bioavailability. The limitations of these studies include a failure to provide the dose adjusted on a body weight basis, the failure to measure excretion and the failure to measure the EPA and DHA levels in the red blood cells (which are widely regarded as the best measure of EPA + DHA tissue status). Furthermore, because of the known high level of variability in the response of subjects to the same dose of fish oil (as noted by Kohler et al. [25]), these studies have limitations because the data was not adjusted for by gender, body weight or exercise level [26]. In the present rat study, rats were fed to fixed predetermined ration, which was adjusted weekly relative to body weight, for 6 weeks which helped to reduce the variability of the results achieved, increased the statistical power of the test (greater than 80% for the vast majority of data recorded), and ultimately contributed to obtaining more robust, substantiated and more easily interpretable findings.

The possible difference in bioavailability of n-3 LC-PUFA when provided in different edible sources has received some research attention. Specifically, the blood levels of n-3 LC-PUFA derived from daily fish oil capsules compared with either adaily fish meal or daily fish oil enriched food have been reported in a few studies [27-30].

In the current study, the Constant and the Spike treatment showed lower levels of apparent in vivo enzyme activity for elongase, A6 and A5 desaturase compared with the Control treatment. Lower A6 desaturase activity with fish oil feeding has been previously reported [31]; however, there is no data looking at a weekly vs. daily dose to compare with. These desaturases and elongases are required for the biosynthesis of LC-PUFA and their inter-conversion. High availability of these fatty acids in Constant and the Spike treatment can act via a negative feedback control mechanism and reduce the gene transcription rate and the actual activity of the desaturase and elongase enzymes in these treatments, possibly via sterol regulatory element binding protein (SREBP-1c) [32,33]. On the other hand, the lack of n-3 LC-PUFA intake in the diet of the Control rats has likely increased their elongase and desaturase enzyme activities in order to increase endogenous n-3 LC-PUFA synthesis. Dietary n-3 LC-PUFA deprivation has previously been shown to upregulate liver mRNA levels of A6 and A5 desaturases as well as activities of A6 and A5 desaturases [34,35].

Overall, there were no significant differences in the assessed enzyme activities between the Spike and Constant treatments, with the exception of A9 desaturase (required for the biosynthesis of monounsaturated fatty acids), which was significantly higher in the Spike treatment.

Admittedly, one of the limitations of the present study includes being an animal study in male rats. Nevertheless, these preliminary, novel and highly interesting findings warrant further investigations, and in particular the need to be substantiated by conducting appropriate trials in humans. It is worth noting that the dose of n-3 LC-PUFA used in the Constant treatment equates to 1012 mg/day for a 70 kg human [36], which is in the range of human recommendations for these fatty acids. Another limitation, as previously mentioned, was that the slightly different total amounts of n-3 LC-PUFA administered by the two n-3 LC-PUFA enriched dietary treatments used in this study. However, these differences are relatively minimal, and unlikely to be responsible of any major modification in the overall n-3 LC-PUFA metabolism, and have been accounted for in the Whole Body Fatty Acid Balance Method. A third limitation is that these results do not apply to comparative effects of consumption of daily fish oil capsules vs. a sporadic meal with fish or seafood, since the study investigated the bioavailability of the same food source of n-3 LC-PUFA; but this was intentional to exclude the possible effect of the matrix (food source) of the dietary n-3 LC-PUFA.

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In conclusion

Our data show that there was a significantly greater deposition of the n-3 LC-PUFA associated with a single large dose of dietary n-3 LC-PUFA compared with the smaller daily doses in rats, due to less -oxidation and greater deposition, and not due to differences in excretion (digestibility). The results from this animal study provide a suitable platform for future human studies aimed at developing substantiated evidence for advising consumers on the most efficient way to increase their n-3 LC-PUFA status. These findings suggests that a large dose of n-3 LC-PUFA once per week is more effective in increasing whole body n-3 LC-PUFA content compared to a smaller dose delivered daily. This observation, if validated in humans, could have remarkable effects on the possible development of more effective and sustainable utilisation strategies of these limited and metabolically important nutrients, currently derived primarily from the dwindling oceanic fish stocks.

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Perplexity AI – Deep Research read the rat study and thought resi;ts might apply to humans as well – March 2025

Weekly vs. Daily Omega-3 Supplementation: Insights from Rat Research and Human Implications The search for optimal nutrient intake strategies continues to evolve as researchers explore not just how much of a nutrient we need, but how the timing and frequency of consumption affects its utilization in the body. A fascinating study by Ghasemifard and colleagues has uncovered potentially significant findings regarding omega-3 fatty acid supplementation that challenges conventional wisdom about daily supplement regimens.

The Rat Study: Comparing Weekly and Daily Omega-3 Intake
The research examined whether consuming the same total amount of omega-3 fatty acids—specifically EPA (eicosapentaenoic acid), DPA (docosapentaenoic acid), and DHA (docosahexaenoic acid)—on a different schedule would affect how the body processed these important nutrients. The experiment compared rats receiving a constant daily dose of fish oil (Constant treatment) to those receiving the same weekly total amount but delivered as a single larger dose once per week (Spike treatment).

The results were surprising and potentially significant. The study found that rats receiving the weekly dose had significantly greater deposition of omega-3 fatty acids in their tissues compared to those receiving daily doses. Specifically, rats in the Spike treatment deposited 23% of their omega-3 intake into tissues, while those in the Constant treatment only deposited 15%. Conversely, rats receiving daily doses metabolized (β-oxidized) more of their omega-3 intake (84%) compared to those receiving weekly doses (75%).

This suggests that the large weekly dose resulted in better "bioavailability" of omega-3s, as more fatty acids were incorporated into body tissues rather than being used for energy. The researchers proposed that a large bolus dose might saturate the body's capacity to metabolize these fatty acids, resulting in greater tissue retention.

Differences Among Specific Omega-3 Fatty Acids
The study revealed interesting distinctions in how different omega-3 fatty acids were processed. While EPA was heavily oxidized regardless of dosing schedule, DPA and DHA showed more pronounced differences in metabolism between treatments. With weekly dosing, DPA in particular showed dramatically different metabolic fate—deposition actually exceeded β-oxidation (56.5% deposition vs. 40% oxidation), unlike in the daily dosing group where most DPA was oxidized.

This suggests that not all omega-3s respond the same way to dosing frequency, with the longer-chain DPA and DHA potentially benefiting more from the weekly dosing approach.

Limited Human Evidence: The Research Gap
While the rat study provides compelling evidence for potential benefits of weekly dosing, direct human evidence remains limited. The researchers noted that only two human studies have compared weekly versus daily omega-3 dosing, with mixed results. Harris et al. found no significant differences in EPA and DHA levels in red blood cells or plasma phospholipids between subjects consuming fish twice weekly versus those taking daily fish oil supplements. However, Browning et al. observed higher levels of EPA and DHA in platelets and mononuclear cells with twice-weekly dosing, though plasma phosphatidylcholine levels showed no difference.

These human studies have significant limitations, including failure to adjust doses based on body weight, lack of excretion measurements, and not accounting for variables like gender and exercise level that can affect omega-3 metabolism. Additionally, they didn't always use the ideal biomarkers for assessing omega-3 status.

Physiological Mechanisms and Implications
The researchers hypothesized that the improved deposition with weekly dosing might result from temporarily overwhelming the body's capacity to oxidize omega-3s when they arrive in large amounts. With daily small doses, the body efficiently channels these fatty acids toward energy production pathways. However, when presented with a large bolus dose, some metabolic pathways may become saturated, resulting in more fatty acids being directed toward tissue incorporation.

This has particular relevance for DHA, which is critical for brain and retinal function. If weekly dosing truly improves DHA deposition in tissues, this could have significant implications for neurological and cardiovascular health.

Limitations and Considerations
Several important limitations must be considered when interpreting these findings. The study was conducted in male rats only, not humans. The doses used, while scaled to approximate human recommendations (equivalent to about 1012 mg/day for a 70 kg human), may not translate perfectly across species. Additionally, slight differences in total weekly omega-3 intake between treatments occurred due to manufacturing variability in the experimental diets.

The researchers themselves acknowledge that "these preliminary, novel and highly interesting findings warrant further investigations, and in particular the need to be substantiated by conducting appropriate trials in humans"1. They also note that their results don't necessarily apply to comparing daily supplements versus occasional fish meals, since the same source of omega-3s was used in both treatments.

Conclusion
The findings from this rat study challenge the conventional wisdom that daily supplementation is optimal for increasing tissue levels of omega-3 fatty acids. Instead, they suggest that less frequent, larger doses may actually lead to greater tissue incorporation of these beneficial fats, particularly DPA and DHA.

As the researchers conclude, "These findings suggests that a large dose of n-3 LC-PUFA once per week is more effective in increasing whole body n-3 LC-PUFA content compared to a smaller dose delivered daily." They further note that, "This observation, if validated in humans, could have remarkable effects on the possible development of more effective and sustainable utilisation strategies of these limited and metabolically important nutrients".

For consumers and healthcare practitioners considering omega-3 supplementation strategies, these findings suggest that weekly dosing might potentially be as effective—or even more effective—than daily supplementation. However, definitive recommendations await well-designed human trials that can confirm whether these intriguing results in rats translate to meaningful benefits in humans.