Tuesday, June 19, 2012

Phospholipid or Triglyceride? What's in Your Fish Oil Caps? Only Phospholipid Based DHA+EPA Reduces Fat Cell Growth & Elevated Insulin Levels Despite Obesogenic Diet

Image 1 (Liliyu. 2007): Look no further, DHA+EPA in phospholipid form can be found right around the corner in the salmon-sashimi at your favorite sushi restaurant, for example.
I guess you will already have heard about the "huge quality differences" of different fish oil products, the manufacturers of the more expensive products usually use to justify the price difference to the average no-name fish oil cap from your favorite bulk supplier. You may also remember a previous SuppVersity post on the obviously over-blown problem with oxidized (=rancid) fish oil (see "Some Things Fishy: Oxidized Fish Oil Totally Benign!?"), which - much to the researchers' own surprise, worked just as well as regular, fresh fish oil (Ottestad. 2011). What you will probably not have thought about before, however, is the triglyceride to phospholipid ratio of your fish oil caps (Note: While there are intact phospholipids in raw or barely cooked fish, it is almost certain that most of them are destroyed / damaged in the industrial production of fish oil from the waste products of the fishery industry).

Di- vs. triglyceride - One letter can make all the difference

In a recently published study, Rossmeisl et al. report that the administration of the exact same amount of n-3 polyunsaturated fatty acids, namely docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), either as tri- or diglyceride+pohosphate (as they are characeteristic for all phospholipids) had profoundly different effects on the amelioration of weight gain in a 9 week HFD overfeeding study and the reversal of obesity a second trial in which mice that had been subjected to an obesogenic high fat (+hypercaloric) diet for 4 months received chow that contained a dosage of 30g combined EPA + DHA per kg. With a food intake of ~65g per day and a mean body weight of ~30g (mid-trial) this yields the following rodent + human equivalent doses (HED, calculated for 80kg body weight) for the three treatment groups and two control groups in the overfeeding experiment:
  • control - regular diet
  • HFD - high fat diet (HFD) w/out supplement
  • HFD+30TR - HFD + 0.16g/kg EPA+DHA from triglycerides; HED ~1g / day
  • HFD+10PL - HFD + 0.05g/kg EPA+DHA from phospholipids; HED ~ 0.33g / day
  • HFD+30PL - HFD + 0.16g/kg EPA+DHA from phospholipids; HED ~1g / day

Contrary to their identical ameliorative effects on diet induced weight gain, elevated plasma lipids and blood sugar levels, the triglyceride and phospholipid forms of DHA and EPA exerted very different effects on plasma insulin, adipocyte hypertrophy, hepatic steatosis (beginning NAFLD) and low-grade adipose tissue inflammation.
Figure 1: Body composition and glucose metabolism after 4 month HFD diet and subsequent 9 weeks of over-feeding on diets containing either no (control=100%) or 30g/kg diet DHA+EPA; data expressed relative to control (Rossmeisl. 2012)
As you can see in figure 1 only the phospholipid form of the n-3 polyunsaturated fatty acids reduced adipose tissue growth and hyperinsulinemia. And compared to the regular triglycerides, it also had much more pronounced effects on the accumulation of fat in the liver and the exuberant inflammation in the fat stores (WAT) of the animals.

A higher bioavailability of phosphate-bound EPA+DHA is probably only part of the story

Figure 2: Plasma, liver and white adipose tissue (WAT) levels of triglyceride (TL) and phospholipid varieties of DHA+EPA after 9 weeks on HFD diet with (w3TL or w3PL) or  w/out 30mg/kg chow DHA + EPA (Rossmeisl. 2012)
This is an interesting observation and the most straight forward explanation would actually be that due to their ability to be directly incorporated into the cell membrane the phosphate-bound lipids from the -PLI groups received would have a higher affinity to be incorporated into the liver and/or adipose tissue. And while the latter was not the case (cf. figure 2) the significantly more pronounced accumulation of omega-3 phospholipids in the liver of small critters, appears to confirm this hypothesis - or, as the Rossmeisl et al. put it:
Thus, the superior efficacy of dietary LCn-3 PUFA adminis-tered as phospholipids in terms of counteracting adverse effects of developing obesity was linked to the improved bioavailability of DHA and EPA, and to the accumulation of these fatty acids in phospholipids in metabolically relevant tissues.
If you take a closer look at the data, you will yet realize that the omega-3 content of the adipose tissue (WAT) is still pretty low. Other than in the liver, where the TG/PL ratio was significantly lower, when the animals received a phospholid enriched diet, the n3 concentrations were identical for both groups. A higher bioavailability alone could thus hardly explain the pronounced reduction in WAT inflammation and more importantly the ameliorative effect on adipocyte hypertrophy the researchers observed in the in reversal study.

Additional phospholipid advantage: Greater inhibitory effect on inflammatory ligand production

A closer analysis did yet reveal different / more pronounced downstream effects of the phospholipid treatment on the occurrence of the pro-inflammatory endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide (AEA) and the production of their EPA and DHA derived anti-inflammatory counterparts N-eicosapentaenoylethanolamine (EPEA) and N-docosahexaenoylethanolamine (DHEA). The former, i.e. the reduction of 2AG had already been implicated as one of the fundamental mechanism behind the anti-inflammatory effects of krill oil by Batteta et al. in 2009 (Batteta. 2009) and does - despite its obvious efficacy raise some safety concerns, as the synthetic cannabinoid receptor 1 antagonist rimonabant, which has been used very effectively to treat obesity had to be withdrawn from clinical practice due to intolerable adverse psychiatric side effects (mostly anxiety and/or depression, cf. Moereira. 2009).

Fish is still your goto source for DHA & EPA, as trigs and phospholipids in their natural ratio!

Image 2 (animalcrossingdaily): The fishcow! Well, personally I prefer to eat fish and beef, but if you happen to hit upon one of those, I bet their DHA + EPA content is about as "monstrous" as their overall look ;-)
Whether high doses of phospholipid enriched fish oil, as they are suggested by Rossmeisel et al. as an adjunct "treatment strategy for obesity-associated disorders" that should be preferred over regular triglyceride or ethyl-ester (Lovazza) based n-3 PUFA supplements, due to their to higher bioavailability an efficiacy (Rossmeisl. 2012), would actually produce similar adverse effects is questionable. At dosages corresponding to those used in the study at hand, i.e. 1g per day(!), I would say that this is very unlikely. In view of the still prevalent advice of (pseudo-)experts to start out with at least 5g per day of EPA + DHA, I wouldn't be so sure, though, that we are not already seeing the first "victims" of scientifically unwarranted fish oil overconsumption and subsequent endocannabinoid imbalances complaining of anxiety and chronic fatigue on bulletin boards, where one of the "standard treatments" people will suggest is to "up your fish oil intake"...

For you, as a diligent student of the SuppVersity, active and healthy physical culturist, the results of this study do not really make a difference, anyway. After all, you have always been getting your weekly dose of omega-3 fatty acids from fish, the natural source of both the triglyceride and phospholipid form of DHA and EPA, and grass-fed beef or lamb (even grain-fed beef is a relatively good source of omega-3, by the way, only the ratio of omega-6 to omega-3 is usually higher; cf. Wood. 2004) - didn't you?

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  2. Moreira FA, Crippa JA. The psychiatric side-effects of rimonabant. Rev Bras Psiquiatr. 2009 Jun;31(2):145-53. Review.
  3. Ottestad I, Vogt G, Retterstøl K, Myhrstad MC, Haugen JE, Nilsson A, Ravn-Haren G, Nordvi B, Brønner KW, Andersen LF, Holven KB, Ulven SM. Oxidised fish oil does not influence established markers of oxidative stress in healthy human subjects: a randomised controlled trial. Br J Nutr. 2011 Dec 5:1-12.
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  5. Wood JD, Richardson RI, Nute GR, Fisher AV, Campo MM, Kasapidou E, Sheard PR, Enser M. Effects of fatty acids on meat quality: a review. Meat Sci. 2004 Jan;66(1):21-32.