1. Lipid Messengers
in Obesity Positively
Modulated by
Superba™
Krill Oil
Endocannabinoid Overactivity
and its Modulation by
Omega-3 Fatty Acids with
Potential Benefits for
Metabolic Dysfunctions
Sponsored by
2. Manipulating
Endocannabinoid
Overactivity with Krill Oil
Overview
Due to the combination of unique lipids, among them
omega-3 phospholipids, and the antioxidant astaxanthin,
krill oil has been associated with various positive health
effects. Notably, evidence has accumulated in pre-clinical
andclinicalstudiesthatkrilloilcaninfluenceendocannabi-
noids (EC), a class of lipid-derived signalling agents which
trigger various physiological events in the body.
Inthissynopsis,theresearchontheeffectsofkrilloilonthe
EC system is summarized in order to clarify the potential
impact krill oil may have in helping balance metabolic dis-
turbancesasseeninobesity.Itisproposedthatdietarysup-
plementationwithkrilloildirectlyinfluencestheproduction
of ECs. Imbalanced activity of the EC system has been
associated with inflammation and with increased appetite
and food intake contributing to the accumulation of fat.
By regulating EC levels, krill oil helps to restore balance in
the endocannabinoid system, which can impede the devel-
opment of metabolic disorders such as obesity and
obesity-associatedconditionssuchastype-2diabetesand
certain aspects of coronary heart disease.
Endocannabinoid system and obesity
Globally there are more than 1.5 billion overweight adults
and at least 500 million of them are obese [1]
. Being over-
weightorobesenegativelyimpactsbloodpressure,triglyc-
erides, cholesterol, and insulin resistance, increasing the
risks for cardiovascular diseases, type 2 diabetes, some
cancers, and osteoarthritis.
Obesity and its health consequences are associated with a
dysregulated endocannabinoid signalling system that is
chronicallyactivated.Itisbasedontheactionofendogenous
cannabinoids, called endocannabinoids (ECs), and the
receptors they can bind to and activate.The binding of ECs
to receptors influences intracellular gene expression in
peripheral tissues (e.g. liver, skeletal muscle, pancreas,
intestine, bone, and adipose tissue) and modulates the
action of the central nervous system. Thereby they can
influence not only enzyme activities, but also appetite,
energy balance, mood, memory, pain perception, immune
functions, and reproductive processes (Figure 1). An over-
active EC system was suggested to promote increased fat
massandvariousparametersofthemetabolicsyndrome[2]
.
Two of the most studied ECs that show elevated blood
levels in obesity are called N-arachidonoyl-ethanolamine
(AEA;anandamide)and2-arachidonoylglycerol(2-AG).They
are derived from arachidonic acid in membrane lipids by
enzymatic reactions. While arachidonic acid bound to the
1-position of phospholipids is converted into AEA, arachi-
donic acid esterified to the 2-position of phospholipids is
themostcommonprecursorfor2-AG.ThequantitiesofAEA
and 2-AG made ultimately depend on the amounts of
arachidonic acid available at the 1- and 2-positions of
phospholipids, respectively.
Arachidonic acid belongs to the omega-6 family of fatty
acids that distinguishes itself from omega-3 fatty acids by
the position of the first double bond. Increased intake of
fatty acids of the omega-3 family positively influences the
ratioofomega-3toomega-6fattyacidsinbloodandorgans
insuchawaythatlessarachidonicacidisincorporatedinto
phospholipids, possibly resulting in decreased conversion
of arachidonic acid to AEA and 2-AG. Thus, dietary fatty
acids present a means to change the body’s fatty acid
composition and thereby EC levels, ultimately affecting
membranesignallingeventsandleadingtochangedenergy
metabolism (food intake and energy processing).
Krill, a source of omega-3 fatty acids
One rather novel source of omega-3 fatty acids with the
ability to decrease the synthesis of ECs, is found in
Superba™ Krill oil. Krill oil is extracted from the Antarctic
crustacean Euphausia superba (Figure 2). Krill live in huge
swarms and are one of the most abundant species on
earth. Harvesting of krill is highly restricted to ensure
sustainability and availability to predator species.
Manipulating Endocannabinoids
Fig 1. Effects of receptor activation by endocannabinoids on some
selected tissues. FA, fatty acid;TG, triglyceride.
3. Krilloilhasacharacteristicredcolorduetothepresenceof
astaxanthin. Astaxanthin is a powerful antioxidant that is
taken up by krill when they feed on algae that produce it.
Equally,theomega-3fattyacidsfoundinalgaeareincorpo-
rated by the krill, which subsequently can be extracted in
krill oil.
In contrast to fish oil, which contains omega-3 fatty acids
bound to triglycerides, krill oil provides its omega-3 fatty
acids mainly in the form of phospholipids. Phospholipids
and triglycerides belong to two different classes of lipids.
Both have fatty acids bound to a glycerol backbone.
However, the triglyceride molecule is heavily nonpolar in
naturewiththreefattyacidsboundtoaglycerolbackbone.
Phospholipids are bipolar as they have on one side a polar
head group consisting of a phosphate and an organic
molecule, and on the other two fatty acid chains bound to
glycerol (Figure 3).
Due to these special characteristics, phospholipids have
the ability to form membranes. It was suggested in two
human clinical studies that the molecular form (phospho-
lipids versus triglycerides) to which omega-3 fatty acids
are attached is the reason for a higher increase in omega-3
levels in the blood of subjects treated with Superba™ Krill
oil compared to in subjects given fish oil [3, 4]
.This structural
difference in presenting omega-3 fatty acids might also
account for the more pronounced effect on influencing
EC levels seen after Superba™ Krill oil administration in
comparison to fish oil supplementation.
Positive effects of krill oil on endocannabinoid levels
Zucker rats, a model for obesity and its related metabolic
dysfunctions, were given low dose Superba™ Krill oil sup-
plementations for four weeks [5]
. Tissue EC concentrations
were measured in adipose tissue, liver, and heart. Batetta
andco-workersfoundthatAEAand2-AGaroundtheorgans
in visceral adipose tissue (VAT) were lowered by krill oil in-
take in comparison to a control group, but not beneath the
skin in subcutaneous adipose tissue (SAT).
Moreover, the EC, AEA but not 2-AG, was reduced in both
liver and heart in the Superba™ Krill oil group compared to
the control group. Additionally, both the liver and heart
triglyceride concentrations decreased significantly after
supplementation with krill oil compared to the control
group. This is in line with previous findings that AEA is
responsiblefortriglycerideliverdepositioninrodents.Not
onlywereECconcentrationsinVAT,liver,andheartafterkrill
oil intake modulated, but also plasma LDL-cholesterol
concentrations were decreased, and the secretion of the
inflammatory molecule,TNFα, from white blood cells were
found to be reduced in this study. In this short-term
experiment, no change in body weight could be observed.
However, it is tempting to speculate that a long-term
administration of Superba™ Krill oil leads to lower intra-
abdominal fat. This would be in agreement with the
observations that EC receptor overactivity in rodents and
humans is associated with increased fat accumulation in
this fat depot [5-7]
. Lowered visceral fat and decreased
triglyceride levels in liver and heart would lower the health
risks associated with obesity considerably.
Care should be taken when manipulating the EC signalling
system. It has been established that the EC signalling
systemplaysanimportantroleinbrainfunctionbyallowing
foradequateemotionalresponsesandthecopingtostress,
and that its blockage can lead to anxiety and depression [8]
.
Yet, there is evidence that when attempting to achieve
metabolic benefits in obese individuals, it is sufficient to
induce changes in peripheral EC levels and not affect EC
overactivity in the brain [9]
. A further study has therefore
investigated if Superba™ Krill oil influences EC profiles in
thebrainofZuckerrats[10]
tothesameextentasinperipheral
Manipulating Endocannabinoids
Fig 3. Graphical illustration of phospholipid and triglyceride molecule.
Phospholipidshaveahydrophilic,polarheadgroupandahydrophobictail.
Fig 2. Antarctic krill, Euphausia superba is protected from overfishing by
theCommissionfortheConservationofAntarcticMarineLivingResources
(CCAMLR) with precautionary harvesting limits. photo: Aker BioMarine
4. tissuesdescribedabove[5]
.Theresearchersfoundthatfour
weeks administration of krill oil increased omega-3 levels
in brain phospholipids, with no change in arachidonic acid
content. While AEA was unchanged in the krill oil group,
2-AG levels were reduced in the brain. But as food intake
and feed efficiency remained unchanged in these rats, it
suggests that the decrease of 2-AG levels was not enough
to exert an effect. Most importantly krill oil administration
inducednochangeinAEAlevelsassociatedwiththecontrol
over stress-, anxiety-, and depression-related behaviors.
In an attempt to further uncover the influence of Superba™
Krill oil on the EC system in a wider array of tissues, includ-
ing muscle and kidney, a third study was performed by
Piscitellietal.Differentdosesofkrilloilwereadministered
foreightweekstomiceonahighfatdiet[11]
.Thehighfatdiet
resulted in increased hepatic triglyceride, cholesterol, and
TNFα values on which krill oil exerted beneficial lowering
effects. The high fat diet induced increased levels of 2-AG
inbothmuscleandkidney.Superba™Krilloilhowever,ledto
a decrease of both 2-AG and AEA in these tissues.
Lastly, a clinical study on normal-weight, overweight, and
obesesubjectswasundertakenbyBanniandcolleagues[12]
.
A daily dose of 2g of Superba™ Krill oil was given for four
weeks. It was confirmed that obese subjects have elevated
levels of plasma ECs compared to normal-weight subjects.
The data showed that Superba™ Krill oil was able to
significantly decrease 2-AG in obese subjects that
correlated with a decreased plasma phospholipid
omega-6/omega-3 ratio.
Overall, based on the aforementioned findings, dietary
supplementation with Superba™ Krill oil presents a
promising approach to counteract elevated EC levels only
peripherally, circumventing psychiatric effects associated
with changes in brain EC levels. By changing the balance
between omega-6 and omega-3 fatty acids and reducing
EC precursor availabilities, Superba™ Krill oil may provide
therapeutic benefits such as lowered triglyceride blood
levels and decreased fat deposition in and around organs.
In conclusion, Superba™ Krill oil could alleviate metabolic
dysfunctions such as dyslipidemia, visceral adiposity,
and the associated inflammatory states that play a
role in atherogenesis and the subsequent increased
cardiovascular risk.
Manipulating Endocannabinoids
References
1.World-Health-Organization: Obesity and overweight. Fact sheet 2011.
2.MatiasI,PetrosinoS,RacioppiA,CapassoR,IzzoAA,DiMarzoV:Dysreg-
ulationofperipheralendocannabinoidlevelsinhyperglycemiaandobesity:
Effect of high fat diets. Mol Cell Endocrinol 2008, 286:S66-78.
3. Maki KC, Reeves MS, Farmer M, Griinari M, Berge K, Vik H, Hubacher R,
Rains TM: Krill oil supplementation increases plasma concentrations of
eicosapentaenoic and docosahexaenoic acids in overweight and obese
men and women. Nutr Res 2009, 29(9):609-615.
4. Ulven SM, Kirkhus B, Lamglait A, Basu S, Elind E, HaiderT, Berge K,Vik H,
Pedersen JI: Metabolic effects of krill oil are essentially similar to those
of fish oil but at lower dose of EPA and DHA, in healthy volunteers. Lipids
2011, 46(1):37-46.
5. Batetta B, Griinari M, Carta G, Murru E, Ligresti A, Cordeddu L, Giordano
E,SannaF,BisognoT,UdaSetal:Endocannabinoidsmaymediatetheabil-
ity of (n-3) fatty acids to reduce ectopic fat and inflammatory mediators
in obese Zucker rats. J Nutr 2009, 139(8):1495-1501.
6. Bluher M, Engeli S, Kloting N, Berndt J, Fasshauer M, Batkai S, Pacher P,
Schon MR, Jordan J, Stumvoll M: Dysregulation of the peripheral and
adipose tissue endocannabinoid system in human abdominal obesity.
Diabetes 2006, 55(11):3053-3060.
7.CoteM,MatiasI,LemieuxI,PetrosinoS,AlmerasN,DespresJP,DiMarzoV:
Circulating endocannabinoid levels, abdominal adiposity and related
cardiometabolic risk factors in obese men. Int J Obes (Lond) 2007,
31(4):692-699.
8.DiMarzoV,DespresJP:CB1antagonistsforobesity–whatlessonshave
we learned from rimonabant? Nat Rev Endocrinol 2009, 5(11):633-638.
9. Tam J, Vemuri VK, Liu J, Batkai S, Mukhopadhyay B, Godlewski G,
Osei-Hyiaman D, Ohnuma S, Ambudkar SV, Pickel J et al: Peripheral CB1
cannabinoid receptor blockade improves cardiometabolic risk in mouse
models of obesity. J Clin Invest 2010, 120(8):2953-2966.
10. Di Marzo V, Griinari M, Carta G, Murru E, Ligresti A, Cordeddu L,
Giordano E, Bisogno T, Collu M, Batetta B et al: Dietary krill oil increases
docosahexaenoic acid and reduces 2-arachidonoylglycerol but not
N-acylethanolaminelevelsinthebrainofobeseZuckerrat.IntDairyJ2010,
20:231.
11. Piscitelli F, Carta G, Bisogno T, Murru E, Cordeddu L, Berge K, Tandy S,
CohnJS,GriinariM,BanniSetal:Effectofdietarykrilloilsupplementation
on the endocannabinoidome of metabolically relevant tissues from high
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12. Banni S, Carta G, Murru E, Cordeddu L, Giordano E, Sirigu AR, Berge K,
Vik H, Maki KC, Di Marzo V et al: Krill oil significantly decreases
2-arachidonoylglycerolplasmalevelsinobesesubjects.NutrMetab(Lond)
2011, 8(1):7.
![Manipulating
Endocannabinoid
Overactivity with Krill Oil
Overview
Due to the combination of unique lipids, among them
omega-3 phospholipids, and the antioxidant astaxanthin,
krill oil has been associated with various positive health
effects. Notably, evidence has accumulated in pre-clinical
andclinicalstudiesthatkrilloilcaninfluenceendocannabi-
noids (EC), a class of lipid-derived signalling agents which
trigger various physiological events in the body.
Inthissynopsis,theresearchontheeffectsofkrilloilonthe
EC system is summarized in order to clarify the potential
impact krill oil may have in helping balance metabolic dis-
turbancesasseeninobesity.Itisproposedthatdietarysup-
plementationwithkrilloildirectlyinfluencestheproduction
of ECs. Imbalanced activity of the EC system has been
associated with inflammation and with increased appetite
and food intake contributing to the accumulation of fat.
By regulating EC levels, krill oil helps to restore balance in
the endocannabinoid system, which can impede the devel-
opment of metabolic disorders such as obesity and
obesity-associatedconditionssuchastype-2diabetesand
certain aspects of coronary heart disease.
Endocannabinoid system and obesity
Globally there are more than 1.5 billion overweight adults
and at least 500 million of them are obese [1]
. Being over-
weightorobesenegativelyimpactsbloodpressure,triglyc-
erides, cholesterol, and insulin resistance, increasing the
risks for cardiovascular diseases, type 2 diabetes, some
cancers, and osteoarthritis.
Obesity and its health consequences are associated with a
dysregulated endocannabinoid signalling system that is
chronicallyactivated.Itisbasedontheactionofendogenous
cannabinoids, called endocannabinoids (ECs), and the
receptors they can bind to and activate.The binding of ECs
to receptors influences intracellular gene expression in
peripheral tissues (e.g. liver, skeletal muscle, pancreas,
intestine, bone, and adipose tissue) and modulates the
action of the central nervous system. Thereby they can
influence not only enzyme activities, but also appetite,
energy balance, mood, memory, pain perception, immune
functions, and reproductive processes (Figure 1). An over-
active EC system was suggested to promote increased fat
massandvariousparametersofthemetabolicsyndrome[2]
.
Two of the most studied ECs that show elevated blood
levels in obesity are called N-arachidonoyl-ethanolamine
(AEA;anandamide)and2-arachidonoylglycerol(2-AG).They
are derived from arachidonic acid in membrane lipids by
enzymatic reactions. While arachidonic acid bound to the
1-position of phospholipids is converted into AEA, arachi-
donic acid esterified to the 2-position of phospholipids is
themostcommonprecursorfor2-AG.ThequantitiesofAEA
and 2-AG made ultimately depend on the amounts of
arachidonic acid available at the 1- and 2-positions of
phospholipids, respectively.
Arachidonic acid belongs to the omega-6 family of fatty
acids that distinguishes itself from omega-3 fatty acids by
the position of the first double bond. Increased intake of
fatty acids of the omega-3 family positively influences the
ratioofomega-3toomega-6fattyacidsinbloodandorgans
insuchawaythatlessarachidonicacidisincorporatedinto
phospholipids, possibly resulting in decreased conversion
of arachidonic acid to AEA and 2-AG. Thus, dietary fatty
acids present a means to change the body’s fatty acid
composition and thereby EC levels, ultimately affecting
membranesignallingeventsandleadingtochangedenergy
metabolism (food intake and energy processing).
Krill, a source of omega-3 fatty acids
One rather novel source of omega-3 fatty acids with the
ability to decrease the synthesis of ECs, is found in
Superba™ Krill oil. Krill oil is extracted from the Antarctic
crustacean Euphausia superba (Figure 2). Krill live in huge
swarms and are one of the most abundant species on
earth. Harvesting of krill is highly restricted to ensure
sustainability and availability to predator species.
Manipulating Endocannabinoids
Fig 1. Effects of receptor activation by endocannabinoids on some
selected tissues. FA, fatty acid;TG, triglyceride.](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)