Marine omega-3 fatty acids: protection from metabolic syndrome?
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Obesity and being overweight are associated with a large number of medical complications that increase the health burden on individuals and society as a whole. The cultural perception of what a normal body should look like is closely linked to being overweight. Adipose tissue is responsible for creating what we regard as physical beauty by smoothing out the angles and grooves of the body where muscle and bones cross or meet. Sometimes, these cells do that job a little too well and the body form becomes too round. Sixty million people in the USA are obese; but, although this is a large number, it is still only a fraction of the total that would like to be slimmer. Body sculpting has become a prerequisite for being successful and a substitute for happiness. Beautiful skin and well-trimmed muscles have become the ideal, and fat tissue should be reduced by any means. This very negative perception of fat tissue does not necessarily promote a healthy lifestyle, however, as fat cells are an important contributor to a number of bodily functions. The challenge lies in finding the cut-off point between what is good for you and what you would like to see in the bathroom mirror.
Even though one billion people in the world are starving, the medical problems associated with overeating are comparatively more important. Not only is too much food available, people are also eating the wrong type of food. And, as we exercise too little, we utilize the depot function extensively. In addition to nutrient storage and their effect on body shape, fat cells or adipocytes provide an important cushioning role for visceral organs and the eyeball. Fat surrounds organs such as the kidneys, testes, ovaries and lymph nodes, protecting them from physical damage. If we look at fat tissue through a microscope, adipocytes look like small, empty drops (Figure 1). However, in an electron microscope image (Figure 2), we can see that the cell wall contains a nucleus, as well as organelles that are responsible for producing energy, and proteins, indicating that adipocytes are fully developed cells that are capable of producing metabolic energy as well as bioactive compounds. In fact, fat cells not only serve as a fat reservoir, they also produce compounds that control hunger and satiety. The hormone leptin decreases appetite and, up to a certain cell size, fat cells produce more leptin to curtail food intake. Therefore, rather than contributing to disease, adipocytes normally function as part of the immune system and help to control lipid accumulation. They are, as such, actually beneficial to human health. But when fat cells are distended or overloaded beyond a critical level, they become dysfunctional and things start to go wrong. It is important to realize that adipocytes can be functional and beneficial without creating obesity. The point is that we want (and need) plenty of adipocytes to meet the immunological and endocrinological requirements they fulfil, but we do not want them to over-accumulate lipid.
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When Cytokines Attack
Fat cells are not just a burden; they're essential to normal life. In contrast to the present Sisyphus paradigm of fat tissue reduction by any means, fat cells are necessary for metabolism and the control of hunger and satiety. Small abdominal fat cells are ready to absorb surplus calories. If they are chronically overfilled with fat, this ability is lost. The fat tissue factor that is linked to disease is the amount of lipid, or triglycerides, that is saved in the fat cells. As adipocytes accumulate excess lipid, they start to degenerate and their normal function is distorted. Degeneration creates signals that attract inflammatory cells, such as macrophages that gather around the cells (Figure 3). Macrophages have the ability to produce cell-toxic cytokines that are meant to destroy bacteria and cancer cells. Surrounding degenerating adipocytes, the macrophages release cytokines--mainly TNF-alpha and Interleukin-1--into the systemic circulation, creating the so-called silent inflammation that can be detected in people who are obese or overweight. This chronic state of inflammation is a hallmark of metabolic syndrome, adding to the increased risk profile of obese people.
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There is also a link between the immune system, obesity and so-called insulin resistance. Cytokines may be fundamentally linked to the development of insulin resistance. Resistin, another hormone produced by fat cells, prompts other tissues such as muscle to resist insulin. In addition, cells overfilled with triglycerides lead to the deposition of fat into tissues that are not designed to receive lipids, such as the liver and muscle, which is another important mechanism in the development of insulin resistance. People with Type 2 diabetes do produce insulin, at least in the initial phase, but the insulin cannot control their glucose levels because of a lack of insulin sensitivity in tissues where glucose is utilized. Adipocytes normally produce substances that promote the insulin regulation of glucose levels, but these factors do not function properly in the obese. In fact, fat cells use a series of messengers to communicate with liver and muscle cells. Adipose tissue appears to be more than capable of telling other energy producing organs what to do. Adipose tissue, once thought to function primarily as a passive depot for the storage of excess lipid, is now understood to play a much more active role in metabolic regulation, secreting a variety of hormones that act on metabolism, thereby actively serving to prevent metabolic disease.
Feel the Burn
Of course, overloading fat cells with triglycerides can be prevented by eating less and exercising more. However, another mechanism to prevent lipid accumulation is the genetic activation of lipid oxidation--increased 'fat burning.' Several genes carry the code for proteins that increase fatty acid oxidation. These genes are equipped with so-called nuclear receptors that bind fatty components as ligands. When these ligands bind tightly to the receptor, protein transcription is initiated. Food-based fatty acids derived from triglycerides and phospholipids bind to nuclear receptors such as the peroxisome proliferator activating receptor (PPAR). PPAR??and PPAR? are the most important receptors linked to the metabolism of fat and glucose. Studies of metabolic syndrome in an animal model have demonstrated that the marine omega-3 fatty acid, docosahexaenoic acid (DHA), increased fatty acid oxidation, probably through the genetically induced proliferation of cell organelles where metabolic energy and heat are produced, namely mitochondria and peroxisomes. (1) Figure 4 shows the proliferation of mitochondria in animals given DHA. Studies of these animals demonstrated higher lipid oxidation and reduced abdominal fat volume, but not subcutaneous fat. (2) Insulin resistance and fat liver content was also normalized (Figure 5), although the effect on overall weight was not always significant. Correspondingly, abdominal adipocyte size was significantly reduced in animals given DHA, but not in the controls given only a high fat diet (Figure 6).
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This pattern illustrates that a diet enriched in DHA from marine sources could reduce the overload and thereby the size of abdominal fat cells, probably by gene-activated fat oxidation. The abdominal fat cells seem to be very responsive in this respect. Subcutaneous cells, however, were not affected at all, which probably explains why there was no difference in weight gain between DHA-treated animals and the controls. Overloaded abdominal fat cells can reduce their content by genetic activation using marine omega-3 fatty acids. DHA induces fatty acid oxidation, thereby reducing the fat content of these cells and making them shrink. This could be achieved without significant weight reduction.
The DHA Solution
Clinical studies on weight reduction in obese humans as a result of taking omega-3 fatty acids, either by eating fish or omega-3 capsules, or by taking omega-3 concentrated DHA capsules, have produced conflicting results, although some weight loss has been demonstrated. (3-7) However, one clinical study showed the same interesting pattern as in adipose-prone animals regarding small adipocytes. (8) Abdominal tissue biopsies from 59 people were examined with respect to cell size, insulin sensitivity and the mRNA expression of lipidogenic genes responsible for fat cell lipid synthesis. People with large adipocytes had high insulin resistance. Interestingly, their body mass index (BMI) did not correlate with fat cell size. At the same time, mRNA levels for lipidogenic genes were reduced in people with large fat cells. First, this means that people in general may have adipocytes of different sizes and that those who have large fat cells may be more susceptible to developing insulin resistance and, therefore, metabolic syndrome. Some people may be genetically disposed to have more small fat cells than others and they may, as such, be protected from fat overload and the subsequent consequences. However, if humans react in the same way as mice, large fat cells can shrink by genetic modification as a result of DHA use. Increased lipid oxidation would make fat cells restitute and recapture their ability to regulate insulin sensitivity, even without significant weight reduction, thereby preventing the development of metabolic syndrome. If this holds true, a healthy strategy could be to eat more seafood or take a marine DHA concentrate to reduce fat cell size and regain metabolic control--without necessarily losing weight.
Clearly, we absolutely need our lipid cells. Lipodystrophy is a rare disorder characterized by a loss of adipose tissue. Strangely enough, metabolic complications such as insulin resistance, diabetes mellitus, hypertriglyceridaemia and fatty liver increase in severity as fat loss increases, and many people even develop Type 2 diabetes. These patients have, on the whole, lost metabolic control of their fat tissue and are a negative example of what extreme weight loss can lead to. Diabetes is one of the leading causes of death and disability in the world. An estimated 16 million people in the USA have diabetes. The long-term negative effects of the disease are blindness, heart attacks, atherosclerosis, peripheral blood vessel disease, strokes, kidney failure, amputations and nerve damage. About 90% of diabetic cases today are Type 2 diabetes and approximately 80% of people with Type 2 diabetes are overweight. Approximately 100 million people in the USA are overweight, and many are therefore probably at risk of already having developed metabolic syndrome, which is a precursor stage to Type 2 diabetes. Even children are at risk; 15% of children aged between 6 and 14 are overweight in the USA. And there is a 10% increase for every 10 years of age. Dietary measures and exercise should be mandated, not just to lose weight but also to reduce the fat load of abdominal adipocytes so that they can regain metabolic control. Clearly, seafood is important if this goal is to be reached, and it seems that the marine omega-3 fatty acid DHA could be very effective in this respect.
(1.) P. Flachs, et al., "Cellular and Molecular Effects of n-3 Polyunsaturated Fatty Acids on Adipose Tissue Biology and Metabolism," Clin. Sci. (Lond.) 116(1), 1-16 (2009).
(2.) M. Rossmeisl, et al., "Prevention and Reversal of Obesity and Glucose Intolerance in Mice by DHA Derivatives," Obesity 17, 1023-1031 (2009).
(3.) T.A. Mori, et al., "Dietary Fish as a Major Component of a Weight-Loss Diet: Effects on Serum Lipids, Glucose and Insulin Metabolism in Overweight Hypertensive Subjects," Am. J. Clin. Nutr. 70, 817-825 (1999).
(4.) A. Ramel, et al., "Moderate Consumption of Fatty Fish Reduces Diastolic Blood Pressure in Overweight and Obese European Young Adults During Energy Restriction," Nutrition (published online 1 June 2009).
(5.) M. Kratz, et al., "Dietary n-3 Polyunsaturated Fatty Acids and Energy Balance in Overweight or Moderate Obese Men and Women: A Randomized Controlled Clinical Trial," Nutr. Metab. 6, 1-24 (2009).
(6.) M. Kunesova, et al., "The Influence of n-3 PUFA and Very Low Calorie Diet During a Short-Time Weight Reduction Regimen on Weight Loss and Serum Fatty Acid Composition in Severely Obese Women," Physiol. Res. 55, 63-72 (2006).
(7.) M. Kunesova, et al., "Effects of n-PUFA Combined with Weight Loss Management in Moderately Obese Women," abstract presented at the European Congress on Obesity (Geneva, Switzerland, 14-17 May 2008).
(8.) R. Roberts, et al., "Markers of De Novo Lipogenesis in Adipose Tissue: Associations with Small Adipocytes and Insulin Sensitivity in Humans," Diabetologica 52(5), 882-890 (2009).
For more information
Tel. +47 7013 5960
Morten Bryhn, MD, PhD
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|Title Annotation:||health management|
|Publication:||Nutraceutical Business & Technology|
|Date:||Sep 1, 2009|
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