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Lipid Messengers in Obesity Positively Modulated by Superba Krill Oil Endocannabinoid Overactivity and its Modulation by Omega-3 Fay Acids with Potential Benefits for Metabolic Dysfunctions Sponsored by

Ecb obesity synopsis brochure 2011

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Page 1: Ecb obesity synopsis brochure 2011

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

Page 2: Ecb obesity synopsis brochure 2011

ManipulatingEndocannabinoid Overactivity with Krill OilOverviewDue to the combination of unique lipids, among themomega-3 phospholipids, and the antioxidant astaxanthin,krill oil has been associated with various positive health effects. Notably, evidence has accumulated in pre-clinicaland clinical studies that krill oil can influence endocannabi-noids (EC), a class of lipid-derived signalling agents whichtrigger various physiological events in the body.

In this synopsis, the research on the effects of krill oil on theEC system is summarized in order to clarify the potentialimpact krill oil may have in helping balance metabolic dis-turbances as seen in obesity. It is proposed that dietary sup-plementation with krill oil directly influences the productionof ECs. Imbalanced activity of the EC system has been associated with inflammation and with increased appetiteand food intake contributing to the accumulation of fat.

By regulating EC levels, krill oil helps to restore balance inthe endocannabinoid system, which can impede the devel-opment of metabolic disorders such as obesity and obesity-associated conditions such as type-2 diabetes andcertain aspects of coronary heart disease.

Endocannabinoid system and obesityGlobally there are more than 1.5 billion overweight adultsand at least 500 million of them are obese [1]. Being over-weight or obese negatively impacts blood pressure, triglyc-erides, cholesterol, and insulin resistance, increasing therisks for cardiovascular diseases, type 2 diabetes, somecancers, and osteoarthritis.

Obesity and its health consequences are associated with adysregulated endocannabinoid signalling system that ischronically activated. It is based on the action of endogenouscannabinoids, called endocannabinoids (ECs), and thereceptors they can bind to and activate. The binding of ECsto receptors influences intracellular gene expression inperipheral tissues (e.g. liver, skeletal muscle, pancreas,intestine, bone, and adipose tissue) and modulates theaction of the central nervous system. Thereby they caninfluence not only enzyme activities, but also appetite,energy balance, mood, memory, pain perception, immunefunctions, and reproductive processes (Figure 1). An over-active EC system was suggested to promote increased fatmass and various parameters of the metabolic syndrome [2].

Two of the most studied ECs that show elevated bloodlevels in obesity are called N-arachidonoyl-ethanolamine(AEA; anandamide) and 2-arachidonoylglycerol (2-AG). Theyare derived from arachidonic acid in membrane lipids byenzymatic reactions. While arachidonic acid bound to the1-position of phospholipids is converted into AEA, arachi-donic acid esterified to the 2-position of phospholipids isthe most common precursor for 2-AG. The quantities of AEAand 2-AG made ultimately depend on the amounts ofarachidonic acid available at the 1- and 2-positions ofphospholipids, respectively.

Arachidonic acid belongs to the omega-6 family of fattyacids that distinguishes itself from omega-3 fatty acids bythe position of the first double bond. Increased intake offatty acids of the omega-3 family positively influences theratio of omega-3 to omega-6 fatty acids in blood and organsin such a way that less arachidonic acid is incorporated intophospholipids, possibly resulting in decreased conversionof arachidonic acid to AEA and 2-AG. Thus, dietary fattyacids present a means to change the body’s fatty acidcomposition and thereby EC levels, ultimately affectingmembrane signalling events and leading to changed energymetabolism (food intake and energy processing).

Krill, a source of omega-3 fatty acidsOne rather novel source of omega-3 fatty acids with theability to decrease the synthesis of ECs, is found inSuperba™ Krill oil. Krill oil is extracted from the Antarcticcrustacean Euphausia superba (Figure 2). Krill live in hugeswarms and are one of the most abundant species onearth. Harvesting of krill is highly restricted to ensuresustainability and availability to predator species.

Manipulating Endocannabinoids

Fig 1. Effects of receptor activation by endocannabinoids on someselected tissues. FA, fatty acid; TG, triglyceride.

Page 3: Ecb obesity synopsis brochure 2011

Krill oil has a characteristic red color due to the presence ofastaxanthin. Astaxanthin is a powerful antioxidant that istaken up by krill when they feed on algae that produce it.Equally, the omega-3 fatty acids found in algae are incorpo-rated by the krill, which subsequently can be extracted inkrill oil.

In contrast to fish oil, which contains omega-3 fatty acidsbound to triglycerides, krill oil provides its omega-3 fattyacids mainly in the form of phospholipids. Phospholipidsand triglycerides belong to two different classes of lipids.Both have fatty acids bound to a glycerol backbone.However, the triglyceride molecule is heavily nonpolar innature with three fatty acids bound to a glycerol backbone.Phospholipids are bipolar as they have on one side a polarhead group consisting of a phosphate and an organicmolecule, and on the other two fatty acid chains bound toglycerol (Figure 3).

Due to these special characteristics, phospholipids havethe ability to form membranes. It was suggested in twohuman clinical studies that the molecular form (phospho-lipids versus triglycerides) to which omega-3 fatty acidsare attached is the reason for a higher increase in omega-3

levels in the blood of subjects treated with Superba™ Krilloil compared to in subjects given fish oil [3, 4]. This structuraldifference in presenting omega-3 fatty acids might alsoaccount for the more pronounced effect on influencingEC levels seen after Superba™ Krill oil administration incomparison to fish oil supplementation.

Positive effects of krill oil on endocannabinoid levelsZucker rats, a model for obesity and its related metabolicdysfunctions, were given low dose Superba™ Krill oil sup-plementations for four weeks [5]. Tissue EC concentrationswere measured in adipose tissue, liver, and heart. Batettaand co-workers found that AEA and 2-AG around the organsin visceral adipose tissue (VAT) were lowered by krill oil in-take in comparison to a control group, but not beneath theskin in subcutaneous adipose tissue (SAT).

Moreover, the EC, AEA but not 2-AG, was reduced in bothliver and heart in the Superba™ Krill oil group compared tothe control group. Additionally, both the liver and hearttriglyceride concentrations decreased significantly aftersupplementation with krill oil compared to the controlgroup. This is in line with previous findings that AEA isresponsible for triglyceride liver deposition in rodents. Notonly were EC concentrations in VAT, liver, and heart after krilloil intake modulated, but also plasma LDL-cholesterolconcentrations were decreased, and the secretion of theinflammatory molecule, TNFα, from white blood cells werefound to be reduced in this study. In this short-termexperiment, no change in body weight could be observed.However, it is tempting to speculate that a long-termadministration of Superba™ Krill oil leads to lower intra-abdominal fat. This would be in agreement with theobservations that EC receptor overactivity in rodents andhumans is associated with increased fat accumulation inthis fat depot [5-7]. Lowered visceral fat and decreasedtriglyceride levels in liver and heart would lower the healthrisks associated with obesity considerably.

Care should be taken when manipulating the EC signallingsystem. It has been established that the EC signallingsystem plays an important role in brain function by allowingfor adequate emotional responses and the coping to stress,and that its blockage can lead to anxiety and depression [8].Yet, there is evidence that when attempting to achievemetabolic benefits in obese individuals, it is sufficient toinduce changes in peripheral EC levels and not affect ECoveractivity in the brain [9]. A further study has thereforeinvestigated if Superba™ Krill oil influences EC profiles inthe brain of Zucker rats [10] to the same extent as in peripheral

Manipulating Endocannabinoids

Fig 3. Graphical illustration of phospholipid and triglyceride molecule.Phospholipids have a hydrophilic, polar head group and a hydrophobic tail.

Fig 2. Antarctic krill, Euphausia superba is protected from overfishing bythe Commission for the Conservation of Antarctic Marine Living Resources(CCAMLR) with precautionary harvesting limits. photo: Aker BioMarine

Page 4: Ecb obesity synopsis brochure 2011

tissues described above [5]. The researchers found that fourweeks administration of krill oil increased omega-3 levelsin brain phospholipids, with no change in arachidonic acidcontent. While AEA was unchanged in the krill oil group,2-AG levels were reduced in the brain. But as food intakeand feed efficiency remained unchanged in these rats, itsuggests that the decrease of 2-AG levels was not enoughto exert an effect. Most importantly krill oil administrationinduced no change in AEA levels associated with the controlover 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 byPiscitelli et al. Different doses of krill oil were administeredfor eight weeks to mice on a high fat diet [11]. The high fat dietresulted in increased hepatic triglyceride, cholesterol, andTNFα values on which krill oil exerted beneficial loweringeffects. The high fat diet induced increased levels of 2-AGin both muscle and kidney. Superba™ Krill oil however, led toa decrease of both 2-AG and AEA in these tissues.

Lastly, a clinical study on normal-weight, overweight, andobese subjects was undertaken by Banni and colleagues [12].

A daily dose of 2g of Superba™ Krill oil was given for fourweeks. It was confirmed that obese subjects have elevatedlevels of plasma ECs compared to normal-weight subjects.The data showed that Superba™ Krill oil was able tosignificantly decrease 2-AG in obese subjects thatcorrelated with a decreased plasma phospholipidomega-6/omega-3 ratio.

Overall, based on the aforementioned findings, dietarysupplementation with Superba™ Krill oil presents apromising approach to counteract elevated EC levels onlyperipherally, circumventing psychiatric effects associatedwith changes in brain EC levels. By changing the balancebetween omega-6 and omega-3 fatty acids and reducingEC precursor availabilities, Superba™ Krill oil may providetherapeutic benefits such as lowered triglyceride bloodlevels and decreased fat deposition in and around organs.

In conclusion, Superba™ Krill oil could alleviate metabolicdysfunctions such as dyslipidemia, visceral adiposity,and the associated inflammatory states that play arole in atherogenesis and the subsequent increasedcardiovascular risk.

Manipulating Endocannabinoids

References

1. World-Health-Organization: Obesity and overweight. Fact sheet 2011.

2. Matias I, Petrosino S, Racioppi A, Capasso R, Izzo AA, Di Marzo V: Dysreg-ulation of peripheral endocannabinoid levels in hyperglycemia and obesity: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 ofeicosapentaenoic and docosahexaenoic acids in overweight and obesemen and women. Nutr Res 2009, 29(9):609-615.

4. Ulven SM, Kirkhus B, Lamglait A, Basu S, Elind E, Haider T, Berge K, Vik H,Pedersen JI: Metabolic effects of krill oil are essentially similar to thoseof fish oil but at lower dose of EPA and DHA, in healthy volunteers. Lipids2011, 46(1):37-46.

5. Batetta B, Griinari M, Carta G, Murru E, Ligresti A, Cordeddu L, GiordanoE, Sanna F, Bisogno T, Uda S et al: Endocannabinoids may mediate the abil-ity of (n-3) fatty acids to reduce ectopic fat and inflammatory mediatorsin 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 andadipose tissue endocannabinoid system in human abdominal obesity.Diabetes 2006, 55(11):3053-3060.

7. Cote M, Matias I, Lemieux I, Petrosino S, Almeras N, Despres JP, Di Marzo V:Circulating endocannabinoid levels, abdominal adiposity and relatedcardiometabolic risk factors in obese men. Int J Obes (Lond) 2007,31(4):692-699.

8. Di Marzo V, Despres JP: CB1 antagonists for obesity – what lessons havewe 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 CB1cannabinoid receptor blockade improves cardiometabolic risk in mousemodels 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 increasesdocosahexaenoic acid and reduces 2-arachidonoylglycerol but notN-acylethanolamine levels in the brain of obese Zucker rat. Int Dairy J 2010,20:231.

11. Piscitelli F, Carta G, Bisogno T, Murru E, Cordeddu L, Berge K, Tandy S,Cohn JS, Griinari M, Banni S et al: Effect of dietary krill oil supplementationon the endocannabinoidome of metabolically relevant tissues from highfat-fed mice. Nutrition & Metabolism 2011, 8(1):51.

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-arachidonoylglycerol plasma levels in obese subjects. Nutr Metab (Lond)2011, 8(1):7.

Page 5: Ecb obesity synopsis brochure 2011

US ContactsTodd Norton • [email protected] • (206) 855-6736 x215

Eric Anderson • [email protected] • (206) 855-6736 x217

Europe ContactRoar Hernes • [email protected] • +47 24 13 00 00

Asia ContactChris McReynolds • [email protected] • (206) 660-6756

Aker BioMarine Antarctic US410 Newport Way NW, Suite D, Issaquah, WA 98027

[email protected] (206) 855-6736 or fax (206) 855-6727

Aker BioMarine ASA Fjordallèen 16, 0115 Oslo, Norway

Phone: +47 24 13 00 00

www.superbakrill.com

Superba™ Krill is a trademark of the Aker Group© 2011 Aker BioMarine. All rights reserved.

Manipulating Endocannabinoids