Lipid Messengers in Obesity Positively Modulated by Superba Krill Oil

Transcription

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 and clinical studies that krill oil can influence endocannabinoids (EC), a class of lipid-derived signalling agents which trigger various physiological events in the body. In this synopsis, the research on the effects of krill oil on the EC system is summarized in order to clarify the potential impact krill oil may have in helping balance metabolic disturbances as seen in obesity. It is proposed that dietary supplementation with krill oil directly influences the production 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 development of metabolic disorders such as obesity and obesity-associated conditions such as type-2 diabetes and 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 overweight or obese negatively impacts blood pressure, triglycerides, 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 chronically activated. It is based on the action of endogenous 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 overactive EC system was suggested to promote increased fat mass and various parameters of the metabolic syndrome [2]. Fig 1. Effects of receptor activation by endocannabinoids on some selected tissues. FA, fatty acid; TG, triglyceride. Two of the most studied ECs that show elevated blood levels in obesity are called N-arachidonoyl-ethanolamine (AEA; anandamide) and 2-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, arachidonic acid esterified to the 2-position of phospholipids is the most common precursor for 2-AG. The quantities of AEA 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 ratio of omega-3 to omega-6 fatty acids in blood and organs in such a way that less arachidonic acid is incorporated into 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 membrane signalling events and leading to changed energy 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.

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. Fig 2. Antarctic krill, Euphausia superba is protected from overfishing by the Commission for the Conservation of Antarctic Marine Living Resources (CCAMLR) with precautionary harvesting limits. photo: Aker BioMarine Krill oil has a characteristic red color due to the presence of astaxanthin. Astaxanthin is a powerful antioxidant that is taken up by krill when they feed on algae that produce it. Equally, the omega-3 fatty acids found in algae are incorporated 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 nature with three fatty acids bound to a glycerol backbone. 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). Fig 3. Graphical illustration of phospholipid and triglyceride molecule. Phospholipids have a hydrophilic, polar head group and a hydrophobic tail. Due to these special characteristics, phospholipids have the ability to form membranes. It was suggested in two human clinical studies that the molecular form (phospholipids versus triglycerides) to which omega-3 fatty acids are attached is the reason for a higher increase in omega-3 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 supplementations for four weeks [5]. Tissue EC concentrations were measured in adipose tissue, liver, and heart. Batetta and co-workers found that AEA and 2-AG around the organs in visceral adipose tissue (VAT) were lowered by krill oil intake 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 responsible for triglyceride liver deposition in rodents. Not only were EC concentrations in VAT, liver, and heart after krill 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 intraabdominal 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 system plays an important role in brain function by allowing for 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 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 the brain of Zucker rats [10] to the same extent as in peripheral

4 tissues described above [5]. The researchers found that four 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 induced no change in AEA levels associated with the control 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, including muscle and kidney, a third study was performed by Piscitelli et al. Different doses of krill oil were administered for eight weeks to mice on a high fat diet [11]. The high fat diet 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 in both muscle and kidney. Superba Krill oil however, led to a decrease of both 2-AG and AEA in these tissues. Lastly, a clinical study on normal-weight, overweight, and obese subjects was undertaken by Banni and colleagues [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. References 1. World-Health-Organization: Obesity and overweight. Fact sheet Matias I, Petrosino S, Racioppi A, Capasso R, Izzo AA, Di Marzo V: Dysregulation of peripheral endocannabinoid levels in hyperglycemia and obesity: Effect of high fat diets. Mol Cell Endocrinol 2008, 286:S 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): 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 those of fish oil but at lower dose of EPA and DHA, in healthy volunteers. Lipids 2011, 46(1): Batetta B, Griinari M, Carta G, Murru E, Ligresti A, Cordeddu L, Giordano E, Sanna F, Bisogno T, Uda S et al: Endocannabinoids may mediate the ability of (n-3) fatty acids to reduce ectopic fat and inflammatory mediators in obese Zucker rats. J Nutr 2009, 139(8): 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): Cote M, Matias I, Lemieux I, Petrosino S, Almeras N, Despres JP, Di Marzo V: Circulating endocannabinoid levels, abdominal adiposity and related cardiometabolic risk factors in obese men. Int J Obes (Lond) 2007, 31(4): Di Marzo V, Despres JP: CB1 antagonists for obesity what lessons have we learned from rimonabant? Nat Rev Endocrinol 2009, 5(11): 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): 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-acylethanolamine levels in the brain of obese Zucker rat. Int Dairy J 2010, 20: 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 supplementation on the endocannabinoidome of metabolically relevant tissues from high fat-fed mice. Nutrition & Metabolism 2011, 8(1): 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.

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