Evolutionary Aspects of Diet, the Omega-6/Omega-3 Ratio, and Gene Expression

  1. Post Evolutionary Aspects of Diet, the Omega-6/Omega-3 Ratio, and Gene Expression

    Source: Phytochemicals: Nutrient-Gene Interactions,
    Mark S. Meskin (Editor),
    CRC; 1 edition (February 22, 2006)

    pp 137-159
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    Evolutionary Aspects of Diet, the Omega-6/Omega-3 Ratio, and Gene Expression
    Artemis P. Simopoulos

    • Introduction
    • Evolutionary Aspects of Diet with Emphasis on Omega-6 and Omega-3 Essential Fatty Acids
    • Biological Effects and Metabolic Functions of Omega-6 and Omega-3 Fatty Acids
    • Clinical Intervention Studies and the Omega-6/Omega-3 EFA Balance
    • Omega-3 Fatty Acids and Gene Expression
    • Diet–Gene Interactions: Genetic Variation and Omega-6 and Omega-3
    • Fatty Acid Intake in the Risk for Cardiovascular Disease
    • Conclusions
    • References


    The interaction of genetics and environment, nature and nurture, is the foundation for all health and disease. In the last two decades, using the techniques of molecular biology, it has been shown that genetic factors determine susceptibility to disease and environmental factors determine which genetically susceptible individuals will be affected.1–6 Nutrition is an environmental factor of major importance. Whereas major changes have taken place in our diet over the past 10,000 years since the beginning of the Agricultural Revolution, our genes have not changed. The spontaneous mutation rate for nuclear DNA is estimated at 0.5% per million years. Therefore, over the past 10,000 years there has been time for very little change in our genes, perhaps 0.005%. In fact, our genes today are very similar to the genes of our ancestors during the Paleolithic period 40,000 years ago, at which time our genetic profile was established.7 Genetically speaking, humans today live in a nutritional environment that differs from that for which our genetic constitution was selected. Studies on the evolutionary aspects of diet indicate that major changes have taken place in our diet, particularly in the type and amount of essential fatty acids and in the antioxidant content of foods 7–11 (Table 10.1; Figure 10.1). Using the tools of molecular biology and genetics, research is defining the mechanisms by which genes influence nutrient absorption, metabolism and excretion, taste perception, and degree of satiation — and the mechanisms by which nutrients influence gene expression.

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    The foods that were commonly available to pre-agricultural humans (lean meat, fish, green leafy vegetables, fruits, nuts, berries, and honey) were the foods that shaped modern humans’ genetic nutritional requirements. Cereal grains as a staple food area relatively recent addition to the human diet and represent a dramatic departure from those foods to which we are genetically programmed and adapted.12–17 Cereals did not become a part of our food supply until very recently — 10,000 years ago — with the advent of the Agricultural Revolution. Prior to the Agricultural Revolution humans ate an enormous variety of wild plants, whereas today about 17% of plant species provide 90% of the world’s food supply, with the greatest percentage contributed by cereal grains.12 Three cereals: wheat, maize, and rice together account for 75% of the world’s grain production. Human beings have become entirely dependent upon cereal grains for the greater portion of their food supply. The nutritional implications of such a high grain consumption upon human health are enormous. Cereal grains are high in carbohydrates and omega-6 fatty acids, but low in omega-3 fatty acids and in antioxidants, particularly in comparison to green leafy vegetables. Recent studies show that low-fat, high-carbohydrate diets increase insulin resistance and hyperinsulinemia, conditions that increase the risk for coronary heart disease, hypertension, diabetes, and obesity.18–21 And yet, for the 99.9% of mankind’s presence on this planet, humans rarely or never consumed cereal grains. It is only since the last 10,000 years that humans have consumed cereals. Up to that time, humans were non-cereal-eating hunter-gatherers — since the emergence of Homoerectus 1.7 million years ago. There is no evolutionary precedent in our species for grass seed consumption.7,12 Therefore, we have had little time (<500 generations) — since the beginning of the Agricultural Revolution 10,000 years ago — to adapt to a food type that now represents humanity’s major source of both calories and protein. A number of anthropological, nutritional, and genetic studies indicate that humans’ overall diet, including energy intake and energy expenditure, has changed over the past 10,000 years with major changes occurring during the past 150 years in the type and amount of fat and vitamins C and E intake 7,9,13,22,23,26,27 (Table 10.1 and Table 10.2; Figure 10.1).

    Eaton and Konner 7 have estimated higher intakes for protein, calcium, potassium, and ascorbic acid and lower sodium intakes for the diet of the late Paleolithic period than the current U.S. and Western diets. Most of our food is calorically concentrated in comparison with wild game and the uncultivated fruits and vegetables of the Paleolithic diet. Paleolithic man consumed fewer calories and drank water, whereas today most drinks to quench thirst contain calories. Today industrialized societies are characterized by (1) an increase in energy intake and decrease in energy expenditure; (2) an increase in saturated fat, omega-6 fatty acids, and trans fatty acids, and a decrease in omega-3 fatty acid intake; (3) a decrease in complex carbohydrates and fiber; (4) an increase in cereal grains and a decrease in fruits and vegetables; and (5) a decrease in protein, antioxidants, and calcium intake7,9,22,23,24,25,26 (Table 10.1–Table 10.3). The increase in trans fatty acids is detrimental to health as shown in Table 10.4.28 In addition, trans fatty acids interfere with the desaturation and elongation of both omega-6 and omega-3 fatty acids, further decreasing the amount of arachidonic acid, eicosapentaenoic acid, and docosahexaenoic acid availability for human metabolism.29

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    Food technology and agribusiness provided the economic stimulus that dominated the changes in the food supply.30,31 From per capita quantities of foods available for consumption in the U.S. national food supply in 1985, the amount of eicosapentaenoic acid (EPA) is reported to be about 50 mg per capita/day and the amount of DHA is 80 mg per capita/day. The two main sources are fish and poultry. 32 It has been estimated that the present Western diet is "deficient" in omega-3 fatty acids with a ratio of omega-6 to omega-3 of 15–20/1, instead of 1/1, as is the case with wild animals and, presumably, human beings.7–11,23,33–35 Thus, an absolute and relative change of omega-6 and omega-3 in the food supply of Western societies has occurred over the last 100 years. A balance existed between omega-6 and omega-3 for millions of years during the long evolutionary history of the genus Homo, and genetic changes occurred partly in response to these dietary influences. During evolution, omega-3 fatty acids were found in all foods consumed: meat, wild plants, eggs, fish, nuts, and berries. Recent studies by Cordain et al.36 on wild animals confirm the original observations of Crawford and Sinclair et al.33,37 However, rapid dietary changes over short periods of time as have occurred over the past 100–150 years is a totally new phenomenon in human evolution 23,26,38–40 (Table 10.5).

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    Mammalian cells cannot convert omega-6 to omega-3 fatty acids because they lack the converting enzyme, omega-3 desaturase. Linoleic acid (LA) and alphalinolenic acid (ALA) and their long-chain derivatives are important components of animal and plant cell membranes. These two classes of essential fatty acids (EFA) are not interconvertible, are metabolically and functionally distinct, and often have important opposing physiological functions. The balance of EFA is important for good health and normal development. When humans ingest fish or fish oil, the EPA and docosahexaenoic acid (DHA) from the diet partially replace the omega-6 fatty acids, especially arachidonic acid (AA), in the membranes of probably all cells, but especially in the membranes of platelets, erythrocytes, neutrophils, monocytes, and liver cells. 8 Whereas cellular proteins are genetically determined, the polyunsaturated fatty acid (PUFA) composition of cell membranes is to a great extent dependent on the dietary intake. AA and EPA are the parent compounds for eicosanoid production (Table 10.6, Figure 10.2).

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    Because of the increased amounts of omega-6 fatty acids in the Western diet, the eicosanoid metabolic products from AA, specifically prostaglandins, thromboxanes,leukotrienes, hydroxy fatty acids, and lipoxins, are formed in larger quantities than those formed from omega-3 fatty acids, specifically EPA. The eicosanoids from AA are biologically active in very small quantities, and if they are formed in large amounts, they contribute to the formation of thrombus and atheromas; to allergic and inflammatory disorders, particularly in susceptible people; and to proliferation of cells. Thus, a diet rich in omega-6 fatty acids shifts the physiological state to one that is prothrombotic and proaggregatory, with increases in blood viscosity, vasospasm,and vasoconstriction and decreases in bleeding time. Bleeding time is decreased in groups of patients with hypercholesterolemia, 41 hyperlipoproteinemia, 42 myocardial infarction, other forms of atherosclerotic disease, and diabetes (obesity and hypertriglyceridemia). Bleeding time is longer in women than in men and longer in young than in old people. There are ethnic differences in bleeding time that appear to be related to diet. Table 10.7 shows that the higher the ratio of omega-6/omega-3 fatty acids in platelet phospholipids, the higher the death rate from cardiovascular disease. 43

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    The antithrombotic aspects and the effects of different doses of fish oil on the prolongation of bleeding time were investigated by Saynor et al. 44 A dose of 1.8 g/d EPA did not result in any prolongation in bleeding time, but at 4 g/d the bleeding time increased and the platelet count decreased without any adverse effects. In human studies there has never been a case of clinical bleeding, even in patients undergoing angioplasty while they were on fish oil supplements. 45 There is substantial agreement that ingestion of fish or fish oils has the following effects: platelet aggregation to epinephrine and collagen is inhibited, thromboxane A2 production is decreased, whole blood viscosity is reduced, and erythrocyte membrane fluidity is increased.46–49 Fish oil ingestion increases the concentration of plasminogen activator and decreases the concentration of plasminogen activator inhibitor 1 (PAI-1). 50 In vitro studies have demonstrated that PAI-1 is synthesized and secreted in hepatic cells in response to insulin, and population studies indicate a strong correlation between insulinemia and PAI-1 levels. In patients with types IIb and IV hyperlipoproteinemia and in another double-blind clinical trial involving 64 men aged 35 to 40 years, ingestion of omega-3 fatty acids decreased the fibrinogen concentration. 51 Two other studies did not show a decrease in fibrinogen, but in one, a small dose of cod liver oil was used, 52 and in the other the study consisted of normal volunteers and was of short duration. A recent study noted that fish and fish oil increase fibrinolytic activity, indicating that 200 g/day of lean fish or 2 g of omega-3 EPA and DHA improve certain hematologic parameters implicated in the etiology of cardiovascular disease. 53

    Ingestion of omega-3 fatty acids not only increases the production of prostaglandin I3 (PGI3), but also of PGI2 in tissue fragments from the atrium, aorta, and saphenous vein obtained at surgery in patients who received fish oil two weeks prior to surgery. 54 Omega-3 fatty acids inhibit the production of platelet-derived growth factor (PDGF) in bovine endothelial cells. 55 PDGF is a chemoattractant for smooth muscle cells and a powerful mitogen. Thus, the reduction in its production by endothelial cells, monocytes/macrophages, and platelets could inhibit both the migration and proliferation of smooth muscle cells, monocytes/macrophages, and fibroblasts in the arterial wall. Insulin increases the growth of smooth muscle cells, leading to increased risk for the development of atherosclerosis. Omega-3 fatty acids increase endothelium-derived relaxing factor (EDRF).56 EDRF (nitric oxide) facilitates relaxation in large arteries and vessels. In the presence of EPA, endothelial cells in culture increase the release of relaxing factor, indicating a direct effect of omega-3 fatty acids on the cells.

    Many experimental studies have provided evidence that incorporation of alternative fatty acids into tissues may modify inflammatory and immune reactions and that omega-3 fatty acids, in particular, are potent therapeutic agents for inflammatory diseases. Supplementing the diet with omega-3 fatty acids (3.2 g EPA and 2.2 g DHA) in normal subjects increased the EPA content in neutrophils and monocytes more than sevenfold without changing the quantities of AA and DHA. The antiinflammatory effects of fish oils are partly mediated by inhibiting the 5-lipoxygenase pathway in neutrophils and monocytes and inhibiting the leukotriene B4 (LTB4)- mediated function of LTB5 (Figure 10.2). 57,58 Studies show that omega-3 fatty acids influence interleukin metabolism by decreasing IL-1B and IL-6. 59–62 Inflammation plays an important role in both the initiation of atherosclerosis and the development of atherothrombotic events. 63 An early step in the atherosclerotic process is the adhesion of monocytes to endothelial cells. Adhesion is mediated by leukocyte and vascular cell adhesion molecules (CAMs) such as selectins, integrins, vascular cell adhesion molecule 1 (VCAM-1), and intercellular adhesion molecule 1 (ICAM-1).64 The expression of E-selectin, ICAM-1 and VCAM-1, which is relatively low in normal vascular cells, is upregulated in the presence of various stimuli, including cytokines and oxidants. This increased expression promotes the adhesion of monocytes to the vessel wall. The monocytes subsequently migrate across the endothelium into the vascular intima, where they accumulate to form the initial lesions of atherosclerosis. Atherosclerotic plaques have been shown to have increased CAM expression in animal models and human studies. 65–68 A balance between the omega-6 and omega-3 fatty acids is a more physiologic state in terms of gene expression, 69 eicosanoid metabolism, and cytokine production.

    Further support for the need to balance the omega-6/omega-3 EFA comes from the studies of Ge et al.70 and Kang et al.71 The study by Ge et al. clearly shows the ability of both normal rat cardiomyocytes and human breast cancer cells in culture to form all the omega-3’s from omega-6 fatty acids when fed the cDNA encoding omega-3 fatty acid desaturase obtained from the roundworm C. elegans. The omega-3 desaturase efficiently and quickly converted the omega-6 fatty acids that were fed to the cardiomyocytes in culture to the corresponding omega-3 fatty acids. Thus, omega-6 LA was converted to omega-3 ALA, and AA was converted to EPA, so that at equilibrium, the ratio of omega-6 to omega-3 PUFA was close to 1/1.71 Further studies demonstrated that the cancer cells expressing the omega-3 desaturase underwent apoptotic death, whereas the control cancer cells with a high omega-6/omega-3 ratio continued to proliferate.70 More recently, Kang et al. showed that transgenic mice expressing the C. elegans fat-1 gene encoding an omega-3 fatty acid desaturase are capable of producing omega-3 from omega-6 fatty acids, leading to enrichment of omega-3 fatty acids with reduced levels of omega-6 fatty acids in almost all organs and tissues, including muscles and milk, with no need of dietary omega-3 fatty acid supply.72 This discovery provides a unique tool and new opportunities for omega-3 research and raises the potential of production of fat-1 transgenic livestock as a new and ideal source of omega-3 fatty acids to meet the human nutritional needs.

    (continued below)

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    Source: Phytochemicals: Nutrient-Gene Interactions,
    Mark S. Meskin (Editor),
    CRC; 1 edition (February 22, 2006)

    pp 137-159
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    The Lyon Heart Study was a dietary intervention study in which a modified diet of Crete (the experimental diet) was compared with the prudent diet, or Step I American Heart Association Diet (the control diet).73–75 The experimental diet provided a ratio of LA to ALA of 4/1. This ratio was achieved by substituting olive oil and canola(oil) margarine for corn oil. Since olive oil is low in LA, whereas corn oil is high (8% and 61%, respectively) the ALA incorporation into cell membranes was increased. Cleland et al.76 have shown that olive oil increases the incorporation of omega-3 fatty acids, whereas the LA from corn oil competes. The ratio of 4/1 of LA/ALA led to a 70% decrease in total mortality at the end of two years.73

    The Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico (GISSI) Prevenzione Trial participants were on a traditional Italian diet plus 850 to 882 mg of omega-3 fatty acids at a ratio of 2/1 EPA to DHA.77 The supplemented group had a decrease in sudden cardiac death by 45%. Although there are no dietary data on total intake for omega-6 and omega-3 fatty acids, the difference in sudden death is most likely due to the increase of EPA and DHA and a decrease of AA in cell membrane phospholipids. Prostaglandins derived from AA are proarrhythmic, whereas the corresponding prostaglandins from EPA are not.78 In the Diet and Reinfarction Trial (DART), Burr et al. reported a decrease in sudden death in the group that received fish advice or took fish oil supplements relative to the group that did not.79 Similar results have been obtained by Singh et al.80,81 Studies carried out in India indicate that the higher ratio of Linoleic acid (18:2n-6 ) to A-Linolenic acid (18:3n-3 ) equalling 20/1 in their food supply led to increases in the prevalence of non-insulin dependent diabetes mellitus (NIDDM) in the population, whereas a diet with a ratio of 6/1 led to decreases.82

    James and Cleland have reported beneficial effects in patients with rheumatoid arthritis 83 and Broughton has shown beneficial effects in patients with asthma by changing the background diet.84 James and Cleland evaluated the potential use of omega-3 fatty acids within a dietary framework of an omega-6/omega-3 ratio of 3–4/1 by supplying 4 gm of EPA+DHA and using flaxseed oil rich in ALA. In their studies, the addition of 4 gm EPA and DHA in the diet produced a substantial inhibition of production of IL-1B and TNF when mononuclear cell levels of EPA were equal to or greater than 1.5% of total cell phospholipid fatty acids, which correlated with a plasma phospholipid EPA level equal to or greater than 3.2%. These studies suggest the potential for complementarity between drug therapy and dietary choices that increased intake of omega-3 fatty acids and decreased intake of omega-6 fatty acids may lead to drug-sparing effects. Therefore, future studies need to address the fat composition of the background diet, and the issue of concurrent drug use. A diet rich in omega-3 fatty acids and poor in omega-6 fatty acids provides the appropriate background biochemical environment in which drugs function.

    Asthma is a mediator-driven inflammatory process in the lungs and the most common chronic condition in childhood. The leukotrienes and prostaglandins are implicated in the inflammatory cascade that occurs in asthmatic airways. There is evidence of airway inflammation even in newly diagnosed asthma patients within 2 to 12 months after their first symptoms.85 Among the cells involved in asthma are mast cells, macrophages, eosinophils, and lymphocytes. The inflammatory mediators include cytokines and growth factors (peptide mediators) as well as the eicosanoids, which are the products of AA metabolism, which are important mediators in the underlying inflammatory mechanisms of asthma (Figure 10.2, Table 10.8).

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    Leukotrienes and prostaglandins appear to have the greatest relevance to the pathogenesis of asthma. The leukotrienes are potent inducers of bronchospasm, airway edema, mucus secretion, and inflammatory cell migration, all of which are important to the asthmatic symptomatology. Broughton et al.84 studied the effect of omega-3 fatty acids at a ratio of omega-6/omega-3 of 10/1 to 5/1 in an asthmatic population in ameliorating methacholine-induced respiratory distress. With low omega-3 ingestion, methacholine-induced respiratory distress increased. With high omega-3 fatty acid ingestion, alterations in urinary 5-series leukotriene excretion predicted treatment efficacy and a dose change in >40% of the test subjects (responders), whereas the non-responders had a further loss in respiratory capacity. A urinary ratio of 4-series to 5-series of <1 induced by omega-3 fatty acid ingestion may predict respiratory benefit.

    Bartram et al.86,87 carried out two human studies in which fish oil supplementation was given in order to suppress rectal epithelial cell proliferation and PGE2 biosynthesis. This was achieved when the dietary omega-6/omega-3 ratio was 2.5/1 but not with the same absolute level of fish oil intake and an omega-6/omega-3 ratio of 4/1. More recently, Maillard et al. reported their results on a case control study.88 They determined omega-3 and omega-6 fatty acids in breast adipose tissue and relative risk of breast cancer. They concluded, "our data based on fatty acid levels in breast adipose tissue (which reflect dietary intake) suggest a protective effect of omega-3 fatty acids on breast cancer risk and support the hypothesis that the balance between omega-3 and omega-6 fatty acids plays a role in breast cancer."

    Psychologic stress in humans induces the production of proinflammatory cytokines such as interferon gamma (IFNy), tumor necrosis factor ~ (TNF~), IL-6, and IL-10. An imbalance of omega-6 and omega-3 PUFA in the peripheral blood causes an overproduction of proinflammatory cytokines. There is evidence that changes in fatty acid composition are involved in the pathophysiology of major depression. Changes in serotonin (5-HT) receptor number and function caused by changes in PUFA provide the theoretical rationale connecting fatty acids with the current receptor and neurotransmitter theories of depression.89–91 The increased Arachidonic acid (20:4n-6 )/Eicosapentaenoic acid (EPA) (20:5n-3 ) ratio and the imbalance in the omega-6/omega-3 PUFA ratio in major depression may be related to the increased production of proinflammatory cytokines and eicosanoids in that illness.89 There are a number of studies evaluating the therapeutic effect of EPA and DHA in major depression. Stoll and colleagues have shown that EPA and DHA prolong remission, that is, reduce the risk of relapse in patients with bipolar disorder.92,93

    The above clinical studies in patients with cardiovascular disease, arthritis, asthma, cancer, and mental illness clearly indicate the need to balance the omega-6/omega-3 fatty acid intake for prevention and during treatment. The scientific evidence is strong for decreasing the omega-6 and increasing the omega-3 intake to improve health throughout the lifecycle.94 The scientific basis for the development of a public policy to develop dietary recommendations for essential fatty acids, including a balanced omega-6/omega-3 ratio is robust. 95


    Previous studies have shown that fatty acids released from membrane phospholipids by cellular phospholipases, or made available to the cell from the diet or other aspects of the extracellular environment, are important cell-signalling molecules.96 They can act as second messengers or substitute for the classical second messengers of the inositide phospholipid and the cyclic AMP signal transduction pathways.96 They can also act as modulator molecules mediating responses of the cell to extracellular signals.96 Recently it has been shown that fatty acids rapidly and directly alter the transcription of specific genes.97

    Table 10.9 and Table 10.10 summarize the effects of various PUFA on gene expression. In the case of enzymes involved in carbohydrate and lipid metabolism, both omega-3 and omega-6 fatty acids appear to suppress the genes that encode for several enzymes (Table 10.9), whereas saturated, trans-, and monounsaturated fatty acids fail to suppress. DHA appears more potent in its effect than other PUFA. Omega-6 and omega-3 fatty acids and monounsaturated fatty acids induce acyl-CoA oxidase, the enzyme involved in beta-oxidation, but here again, DHA appears to be more potent.

    In studies of inflammatory cytokines, such as IL-1B, both EPA and DHA suppress IL-1B mRNA whereas AA does not, and the same effect appears in studies on growth related early response gene expression and growth factor (Table 10.10). In the case of VCAM, AA has a modest suppressing effect relative to DHA. The latter situation may explain the protective effect of fish oil toward colonic carcinogenesis, since EPA and DHA did not stimulate protein kinase C.111 PUFA regulation of gene expression extends beyond the liver and includes genes such as adipocyte glucose transporter-4, lymphocyte stearoyl-CoA desaturase 2 in the brain, peripheral monocytes (IL-1B, and VCAM-1), and platelets (PDGF)110 (Table 10.9 and Table 10.10). Whereas some of the transcriptional effects of PUFA appear to be mediated by eicosanoids, the PUFA suppression of lipogenic and glycolytic genes is independent of eicosanoid synthesis and appears to involve a nuclear mechanism directly modified by PUFA. Because of their coordinate or opposing effects, both classes of PUFA are needed in the proper amounts for normal growth and development. Although, so far the studies in infants have concentrated on the effects of PUFA on retinal and brain phospholipid composition and intelligence quotient (IQ),112,113 motor development is very much dependent on intermediary metabolism and on overall normal metabolism, both of which are influenced by fatty acid biosynthesis and carbohydrate metabolism.

    The amounts of PUFA found in breast milk in mothers fed diets consistent with our evolution should serve as a guide to determine omega-6 and omega-3 fatty acid requirements during pregnancy, lactation, and infant feeding. Of interest is the fact that saturated, monounsaturated, and trans fatty acids do not exert any suppressive action on lipogenic or glycolytic gene expression, which is consistent with their high content in human milk serving primarily as sources of energy. Because nutrients influence gene expression, and many chronic diseases begin in utero or in infancy, proper dietary intake of PUFA, even prior to pregnancy may be essential, as shown for folate deficiency in the development of neural tube defects.

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    As discussed above, leukotrienes are inflammatory mediators generated from AA by the enzyme 5-lipoxygenase (Figure 10.2). Since atherosclerosis involves arterial inflammation, Dwyer et al. hypothesized that a polymorphism in the 5-lipoxygenase gene promoter could relate to atherosclerosis in humans, and that this effect could interact with the dietary intake of competing 5-lipoxygenase substrates.114 The study consisted of 470 healthy middle-aged women and men from the Los Angeles Atherosclerosis Study, randomly sampled. The investigators determined 5-lipoxygenase genotypes, carotid-artery intima thickness, markers of inflammation, C-reactive protein (CRP), interleukin-6 (IL-6), dietary AA, EPA, DHA, LA, and ALA, with the use of six 24-hour recalls of food intake. The results showed that 5-lipoxygenase variant genotypes were found in 6% of the cohort. Mean intima-media thickness adjusted for age, sex, height, and racial or ethnic group was increased by 80 ± 19um from among the carriers of two variant alleles as compared with the carrier of the common (wild-type) allele. In multivariate analysis, the increase in intima-media thickness among carriers of two variant alleles (62 um, p = 0.001) was similar in this cohort to that associated with diabetes (64 ìm, p = 0.01), the strongest common cardiovascular risk factor. Increased dietary AA significantly enhanced the apparent atherogenic effect of genotype, whereas increased dietary intake of omega-3 fatty acids EPA and DHA blunted this effect. Furthermore, the plasma level of CRP of two variant alleles was increased by a factor of 2, as compared with that among carriers of the common allele. Thus, genetic variation of 5-lipoxygenase identifies a subpopulation with increased risk for atherosclerosis. The diet–gene interaction further suggests that dietary omega-6 fatty acids promote, whereas marine omega-3 fatty acids EPA and DHA inhibit, leukotriene-mediated inflammation that leads to atherosclerosis in this subpopulation.

    The prevalence of variant genotypes did differ across racial and ethnic groups with higher prevalence among Asians or Pacific Islanders (19.4%), blacks (24%), and other racial or ethnic groups (18.2%) than among Hispanic subjects (3.6%) and non-Hispanic whites (3.1%). Increased intima-mediated thickness was significantly associated with intake of both AA and LA among carriers of the two variant alleles, but not among carriers of the common alleles. In contrast, the intake of marine omega-3 fatty acids was significantly and inversely associated with intima-media thickness only among carriers of the two variant alleles. Diet–gene interactions were specific to these fatty acids and were not observed for dietary intake of monounsaturated, saturated fat, or other measured fatty acids. The study constitutes evidence that genetic variation in an inflammatory pathway — in this case the leukotriene pathway — can trigger atherogenesis in humans. These findings could lead to new dietary and targeted molecular approaches to the prevention and treatment of cardiovascular disease according to genotype, particularly in the populations of non-European descent.


    • Evidence from studies on the evolutionary aspects of diet, modern day hunter-gatherers, and traditional diets indicate that human beings evolved on a diet in which the ratio of omega-6/omega-3 EFA was about 1, whereas in the Western diets the ratio is 15/1 to 16.7/1. Agribusiness and modern agriculture have led to decreases in omega-3 fatty acids and increases in omega-6 fatty acids. Such practices have led to excessive amounts of omega-6 fatty acids, upsetting the balance that was characteristic during evolution when our genes were programmed to respond to diet and other aspects of the environment.

    • LA and ALA are not interconvertible and compete for the rate-limiting Name:  change.gif
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    • AA (omega-6) and EPA (omega-3) are the parent compounds for the production of eicosanoids. Eicosanoids from AA have opposing properties from those of EPA. An increase in the dietary intake of omega-6 EFA changes the physiological state to a prothrombotic, proconstrictive, and proinflammatory state.

    • Many of the chronic conditions — cardiovascular disease, diabetes, cancer, obesity, autoimmune diseases, rheumatoid arthritis, asthma, and depression — are associated with increased production of thromboxane A2 (TXA2), leukotriene B4 (LTB4), IL-1B, IL-6, tumor necrosis factor (TNF), and C-reactive protein. All these factors increase by increases in omega-6 fatty acid intake and decrease by increases in omega-3 fatty acid intake, either ALA or EPA and DHA. EPA and DHA are more potent, and most studies have been carried out using EPA and DHA.

    • In the secondary prevention of cardiovascular disease, a ratio of 4/1 was associated with a 70% decrease in total mortality. A ratio of 2.5/1 reduced rectal cell proliferation in patients with colorectal cancer, whereas a ratio of 4/1 with the same amount of omega-3 PUFA had no effect. The lower omega-6/omega-3 ratio in women with breast cancer was associated with decreased risk. A ratio of 2–3/1 suppressed inflammation in patients with rheumatoid arthritis, and a ratio of 5/1 had a beneficial effect on patients with asthma, whereas a ratio of 10/1 had adverse consequences. These studies indicate that the optimal ratio may vary with the disease under consideration. This is consistent with the fact that chronic diseases are multigenic and multifactorial. Therefore, it is quite possible that the therapeutic dose of omega-3 fatty acids will depend on the degree of severity of disease resulting from the genetic predisposition.

    • Studies show that the background diet, when balanced in omega-6/omega-3, decreases the drug dose. It is therefore essential to decrease the omega-6 intake while increasing the omega-3 in the prevention and management of chronic disease. Furthermore, the balance of omega-6 and omega-3 fatty acids is very important for homeostasis and normal development. The ratio of omega-6 to omega-3 EFA is an important determinant of health, because both omega-6 and omega-3 fatty acids influence gene expression. Recent studies on diet–gene interaction further suggest that dietary omega-6 fatty acids promote, whereas marine omega 3 fatty acids EPA and DHA inhibit leukotriene-mediated inflammation that leads to atherosclerosis.

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    Source: Phytochemicals: Nutrient-Gene Interactions,
    Mark S. Meskin (Editor),
    CRC; 1 edition (February 22, 2006)

    pp 137-159
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    Source: Novel food ingredients for weight control,
    C.J.K. Henry (Editor),
    CRC; 1 edition (May 11, 2007)

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    Omega-3 Fatty Acids and Other Polyunsaturated Fatty Acids and Weight Control
    M. Sörhede Winzell and B. Ahrén, Lund University, Sweden

    13.1 Introduction

    Over the past decades, clinical investigations have evaluated the effects of polyunsaturated fatty acids (PUFAs), with particular interest in the omega-3 (or n-3) PUFAs, and their potential role in preventing metabolic diseases (Simopoulos, 1999, Manco et al., 2004, Riccardi et al., 2004, Nettleton and Katz, 2005). Over the past century, there has been a shift in the type of fat being consumed and today diets contain large amounts of saturated fat, high levels of omega-6 (or n-6) PUFAs and trans-fatty acids. The ratio between omega-6 and omega-3 PUFAs has increased tremendously due to decreased fish consumption in combination with increased intake of omega-6 PUFAs, owing mainly to the use of vegetable oils in cooking.

    High intake of dietary fats, in particular saturated fats, may lead to the development of obesity, insulin resistance and type 2 diabetes (Arner et al., 1991; Taniguchi et al., 1992; Shulman, 2000; Zraika et al., 2002). This seems to be closely connected to the accumulation of triglycerides in non-adipocytes - including hepatocytes, myocytes and pancreatic B-cells - a phenomenon that has been called lipotoxicity (Zhou et al., 2000; Unger, 2003). Lipotoxicity is associated with increased endogenous glucose production from the liver, impaired insulin-stimulated glucose uptake in skeletal muscle and blunted glucose-stimulated insulin secretion from pancreatic cells (Unger and Orci, 2000, Unger and Zhou, 2001). The PUFAs may, however, exert different effects on metabolism, for example: (1) regulating fuel partitioning within the cell by stimulating oxidation and inhibiting lipogenesis; (2) altering membrane stability and fluidity and thereby affecting insulin signalling; (3) regulating gene transcription mainly via fatty acid regulated transcription factors such as the peroxisomal proliferator- activated receptors (PPARs) and the sterol regulatory element binding protein-1 (SREBP-1) (Clarke and Jump, 1994; Krey et al., 1997; Nakatani et al., 2003; Sampath and Ntambi, 2004). PUFAs may therefore have the capacity to prevent or counteract the detrimental effects of high-fat diets on body weight and whole-body metabolism.

    It is important to determine optimal doses of PUFAs for prevention and treatment of metabolic diseases including overweight and obesity. This chapter will focus on the effect of various PUFAs, in particular the omega-3 PUFAs, on the control of body weight and whether dietary supplementation with these fatty acids may improve insulin resistance and type 2 diabetes.

    13.2 Determining the role of omega-3 fatty acids and other polyunsaturated fatty acids in weight control

    The positive effects of omega-3 PUFAs were observed early on among Greenland Inuits, who, despite high fat intake, displayed low mortality from coronary heart disease (Dyerberg et al., 1975). Other epidemiological studies have reported lower prevalence of obesity, type 2 diabetes and cardiovascular diseases in populations consuming large amounts of omega-3 PUFAs from fatty fish (Mouratoff et al., 1969; Kromann and Green, 1980). Subsequent studies have demonstrated that dietary supplementation of omega-3 PUFAs exerts positive effects in several metabolic diseases including coronary heart disease, hypertension, arteriosclerosis, diabetes and inflammatory diseases (Terry et al., 2003; Din et al., 2004; Calder, 2004; Ruxton et al., 2004).

    13.2.1 Definition, structure and metabolism The PUFAs are fatty acids containing two or more double bonds.

    These fatty acids are essential since they cannot be produced in the human body and must therefore be provided in the diet. There are two main types of PUFA, the omega-3 and the omega-6 fatty acids. In the omega-3 PUFAs, the first double bond is located between the third and the fourth carbons, counting from the methyl end of the carbon chain; in the omega-6 PUFA the double bond is located between the sixth and the seventh carbons (Fig. 13.1). Animals cannot, in general, produce omega-3 or omega-6 fatty acids since they lack the enzymes needed for insertion of the double bonds, whereas in plants these fatty acids are produced via 12- and 15- desaturase activity. The simplest members of the omega-6 and omega-3 fatty acids are linoleic acid (18:2n-6) and a-linolenic acid (18:3n-3), respectively (Fig. 13.1). Although mammalian cells do not synthesise linoleic acid and a-linolenic acid, these fatty acids are metabolised by desaturation and elongation reactions (Fig. 13.2). Linoleic acid is converted into y-linolenic acid (18:3n-6), which in turn can be elongated to produce arachidonic acid (20:4n-6) (Fig. 13.2). The same group of enzymes have the ability to metabolise a-linolenic acid and convert it into eicosapentaenoic acid (EPA; 20:5n-3). There is thus a competition between the omega-6 and the omega-3 fatty acids in the enzymatic reactions and also for their metabolisation. The 6-desaturase reaction is the rate-limiting step, and this enzyme has a-linolenic acid as its preferred substrate. In the next reaction step, EPA can be further converted through elongation to docosahexaenoic acid (DHA; 22:6n-3) (Fig. 13.2). These long-chain, more unsaturated forms of linoleic acid and a-linolenic acid are in turn substrates for the production of important biological molecules, which will be discussed later in this chapter.

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    13.2.2 Dietary sources

    The different forms of the PUFAs are found in different food sources (Table 13.1). Plant seed oils like corn oil, sunflower oil and safflower oil are rich in omega-6 PUFAs, constituting up to 75% of the fatty acid content. Most plant oils are richer in omega-6 PUFAs than in omega-3 PUFAs (Table 13.2). Sunflower and safflower oil exist in two different forms, one rich in monounsaturated fat and one rich in PUFAs. Linoleic sunflower oil is available as liquid oil and it is also used in margarine. Because of the high levels of PUFAs in these oils, they are susceptible to oxidation during commercial usage, especially frying, and so they are hydrogenated to a more stable form. Thus, important dietary sources of omega-6 PUFAs are the vegetable oils and margarines. Green plant tissues are rich in a-linolenic acid (18:3n-3), constituting more than 50% of the fatty acids. This is, however, not a significant source of omega-3 PUFAs since the total fat content is very low (Table 13.3). a-Linolenic acid is abundant in plant oils derived from flaxseed, soybean and rapeseed (Table 13.2). The longer forms of omega-3 PUFAs are more readily found in fatty fish like salmon, herring and mackerel, but also are also found in lean fish liver – which contains large amounts of EPA and DHA (Table 13.3). Nuts contain considerable amounts of omega-3 PUFAs and walnuts, in particular, are rich in a-linolenic acid (Feldman, 2002).

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    The composition of dietary fatty acids has changed over the last 100 years (Simopoulos, 1995). The total intake of fat and the amount of saturated fats have increased as well as the omega-6 PUFAs, while the intake of omega-3 PUFAs has decreased. Studies in Palaeolithic nutrition suggest that the hunter–gatherer populations consumed equal amounts of omega-6 and omega-3 PUFAs (Eaton et al., 1998). Today the ratio between these fatty acids is 10–20:1 in the Western diet (Simopoulos, 1999). The reason for the decreased intake of omega-3 PUFAs is mainly a reduced intake of fish. In fact, modern agriculture results in decreased omega-3 PUFA content in many foods – including vegetables, meats, eggs and even in cultured fish – due to the industrial production of animal feed with high contents of omega-6-rich grains (Crawford, 1968, Simopoulos, 1999). The increased amount of omega-6 compared with omega-3 PUFAs in standard diets may have profound effects on human health since studies have indicated that omega-6 PUFAs may shift the physiological status into a prothrombotic, proaggregatory status with increased vasoconstriction and decreased bleeding time (Calder, 2005). The omega-3 PUFAs on the other hand seem anti-inflammatory, antithrombotic and hypolipidaemic, and may thus have beneficial effects in the prevention and/or treatment of several metabolic diseases (Calder, 2005).

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    The dietary PUFA intake is rather similar throughout Western societies. In Sweden and Finland the PUFAs represent around 5% of the total energy consumption (Becker, 1999, Valsta, 1999) and in the United States the intake averages 7%. The omega-3 PUFAs represent ~0.7% of the energy intake, mainly deriving from intake of vegetable oils. The ratio of omega-6 and omega-3 fatty acids is thus approximately 10:1 (Kris-Etherton et al., 2000). The dietary sources of PUFAs are mainly vegetable oils and linoleic acid is the major form, constituting 84–89%, while around 10% are represented by a-linolenic acid. The intake of highly unsaturated PUFAs, like the EPA and DHA found in fatty fish, is low, being 0.1–0.65 g/day in the United States. In the United Kingdom the pattern is similar with increasing consumption of linoleic acid (omega-6) and an estimated omega-3 intake of 0.1–0.5 g/day (Sanders, 2000). However, in Malaysian adults the eating pattern is different. The total fat intake range is 22–26%, while in Western countries it is 35–40%, and the PUFAs constitute only around 4% of the fats. The PUFAs consumed are mainly omega-6 linoleic acid and the omega-6: omega-3 ratio is approximately 10, similar to that in Europe and the United States (Tkw, 1997).

    13.2.3 Food intake and body weight control

    High-fat food intake is considered to be one of the major causes of the development of obesity and obesity-associated insulin resistance (Astrup, 2001; Riccardi et al., 2004). Laboratory animal studies and epidemiological studies in humans have demonstrated that consumption of high-fat dense diets, a typically Western diet, results in insulin resistance and obesity (Storlien et al., 2000; Astrup, 2001; Winzell and Ahren, 2004). There are however, studies indicating that different types of fat have different effects on whole-body energy metabolism and glucose homeostasis, and inclusion of dietary oils containing PUFAs have been proposed to exert positive effects both in patients and in animal models of type 2 diabetes (Malasanos and Stacpoole, 1991; Storlien et al., 1991). There are studies demonstrating that PUFAs, in particular the omega-3 PUFAs (EPA and DHA), are less effective in promoting obesity compared with saturated fats (Shillabeer and Lau, 1994; Azain, 2004). The mechanisms behind these observations probably involve modulation of fuel partitioning since PUFAs down-regulate lipogenesis and stimulate fat oxidation, because these fatty acids regulate the expression of several genes involved in lipid metabolism (Clarke, 2004; Sampath and Ntambi, 2004). Reduction in body fat content has been observed in rodents fed a diet containing fish oil (Ruzickova et al., 2004; Ikemoto et al., 1996), demonstrating that omega-3 PUFAs decreased the visceral fat by inhibiting both hypertrophy and hyperplasia of the fat cells.

    In contrast, the effect of omega-3 PUFA on human body weight control is rather limited. However, in a recent study, overweight men and women were assigned to a daily fish meal, a weight-loss programme or the two in combination for 16 weeks and the effects on body weight and the plasma glucose and lipid profile were investigated (Mori et al., 1999). The fish meal did not in itself reduce the body weight of these obese subjects, but the dietary fish component significantly improved the outcome of the weight-loss programme in that body weight was reduced in combination with improved glucose and insulin levels as well as the serum lipid profile. In another study, 17 subjects (healthy, obese and type 2 diabetic) entered a 5-week diet programme with diets rich in either saturated fats or PUFAs (Summers et al., 2002). Both energy and fat intake appeared to be reduced in the subjects on the PUFA-rich diets, although body weight was not altered. The abdominal subcutaneous fat area was reduced in the group consuming the PUFA-rich diet, and this coincided with improved insulin sensitivity. The results indicate that PUFAs are effective in altering body fat content, which may have beneficial effects on energy metabolism.

    13.2.4 Clinical studies on the effect of polyunsaturated fatty acids on glucose control and dyslipidaemia

    The effect of omega-3 fatty acids on glycaemic control in humans is controversial. Several studies and reviews have indicated that omega-3 PUFAs have adverse effects in that these fatty acids induce elevated basal plasma glucose, and this was particularly pronounced in patients with type 2 diabetes consuming large amounts of fish oil (>10 g fish oil/day) (Borkman et al., 1989; Friday et al., 1989; Vessby, 1989). However, in other studies with lower doses of omega-3 PUFAs, ranging from 1–2 g/day, glucose homeostasis was maintained within normal ranges (Westerveld et al., 1993; Luo et al., 1998; Sirtori et al., 1998). Luo et al. (1998) demonstrated that a moderate intake of omega-3 PUFAs (1.8 g/day) in type 2 diabetic men resulted in a significant reduction in plasma triglyceride levels. There were, however, no effects on fasting glycaemia or HbA1c. During the 2-month study, body weight and energy intake remained stable. In addition, in other studies, which included patients with hypertension and dyslipidaemia, no adverse effects on plasma glucose levels were observed (Grundt et al., 1995; Toft et al., 1995). In both human and animal studies, dietary omega-3 PUFA supplementation was found to result in reduced circulating triglyceride levels, which may be one explanation for the improved insulin sensitivity observed after fish-oil feeding (Mori et al., 1999; Sirtori et al., 1998). The triglyceride-lowering effect is the most consistent and reproducible finding in both animal and human studies with omega-3 PUFAs and fish oil. Two meta-analyses of trials with omega-3 PUFAs or fish oil in patients with type 1 and type 2 diabetics, as well as in healthy controls, demonstrated that dietary fish oils have no statistically significant effect on glycaemic control but the supplementation efficiently reduced plasma triglyceride levels (Friedberg et al., 1998; Montori et al., 2000). There is thus strong evidence suggesting no adverse effects of fish oil or omega-3 PUFAs on glycaemia, and beneficial effects on plasma lipids, when consumed in moderate doses (1–3 g/day).

    Animal studies have demonstrated that various dietary fat subtypes can modulate insulin action indicating that PUFAs have positive effects on insulin sensitivity (Storlien et al., 1991, 2000). One study, where rats were fed isocaloric high-fat diets with different types of fatty acids, demonstrated that diets rich in saturated fat resulted in insulin resistance while rats fed a high level of PUFAs with a low omega-6: omega-3 ratio had normal insulin action (Storlien et al., 1991). It is thus possible that saturated fatty acids affect the cellular membranes in a negative way resulting in impaired insulin action and that this can be prevented by the addition of unsaturated fatty acids to the diet (Ma et al., 2004). PUFAs may thus, at least in animal models, affect glycaemic control by improving insulin sensitivity.

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    13.3 Effects of omega-3 fatty acids and other polyunsaturated fatty acids on energy metabolism and other factors connected to weight control

    The mechanism behind the benefits of omega-3 PUFAs on energy metabolism is at present not completely understood. There are, however, many possibilities since these fatty acids have many different roles in a cell. For example, apart from being an energy source, fatty acids build up the cellular membranes, regulate gene expression and function as signalling molecules and as precursors for complex biologically active molecules such as, for example, eicosanoids (Simopoulos, 1999, Ruxton et al., 2004). Since omega-3 PUFAs exert positive effects in many different diseases there have been implications for a common pathway for the effects. One mechanism that has been presented is the ability of omega-3 PUFAs to affect the biochemical composition of biological membranes (Ma et al., 2004). Indeed, the cellular fatty acids composition is a mirror of the ingested types of fatty acids. Incorporation of PUFAs into lipid membranes results in altered interaction between the lipids and the membrane proteins (Ma et al., 2004). There are, however, other possibilities that need to be considered – including the digestion and absorption of the fatty acids.

    13.3.1 Digestion and absorption of fatty acids

    The length and the degree of saturation of fatty acids influence the biophysical properties of the lipids. This has, for example, effects on the digestion and absorption of the fatty acids from the intestine (Small, 1991). Different sources of fat are composed of different types of triglycerides. Triglycerides are digested in the intestinal lumen by lipases to produce fatty acids and monoacylglycerol and the absorption of fatty acids from the intestinal lumen is generally an efficient process. After absorption, the fatty acids are taken up by the enterocytes where the triglycerides are reconstructed, packed in chylomicrons and very-low-density lipoproteins (VLDLs) and secreted into the lymph. From the lymph, the triglycerides are transported to various capillary beds where they bind to the capillary surface. Here, they are hydrolysed by lipoprotein lipase and the surrounding adipocytes or muscle cells take up the free fatty acids. However, the triglycerides containing long-chain PUFAs like arachidonic acid or EPA are poor substrates for lipoprotein lipase. Instead, they appear to be good substrates for hepatic lipase, and thus acylglycerols containing long-chain PUFAs are returned and metabolised by the liver. To be able to study the uptake and the destiny of the PUFAs, rats were fed purified triglycerides containing oleic acid and long-chain PUFAs (Fahey et al., 1985). The results showed that the uptake of the PUFAs was significantly slower than the uptake of saturated or monounsaturated fatty acids. This demonstrates that the PUFAs are absorbed and metabolised at a lower rate, which may influence both appetite and satiety, two factors that are of great importance in weight control.

    13.3.2 Effect on ectopic lipid accumulation

    Studies in cell culture systems have demonstrated that fatty acids have effects on adipocyte proliferation and differentiation (Azain, 2004). Feeding rats a high-fat diet rich in PUFAs demonstrated no difference in pre-adipocyte replication compared with rats fed a normal diet, while a diet rich in saturated fats accelerated the replication (Shillabeer and Lau, 1994). Furthermore, the size of the adipose tissue was reduced in PUFA-fed rats compared with rats fed saturated fat and this was due to less efficient storage of triglycerides (Shillabeer and Lau, 1994). Thus, the diet containing saturated fat induced expansion of the adipose tissue more efficiently than the diet containing PUFAs; possible mechanisms for these effects are that PUFAs do not induce pre-adipocyte replication to the same extent and are less efficiently incorporated in triglycerides.

    Feeding a diet rich in saturated fats results in accumulation of triglycerides, not only in adipose tissue but also in non-adipocytes and this phenomenon, called lipotoxicity, has been found to correlate to the onset of insulin resistance (Unger, 1995; Boden and Shulman, 2002). There are, however, studies indicating that diets enriched with PUFAs improve insulin sensitivity in both rodents and humans (Storlien et al., 1991; 2000, Summers et al., 2002). One possible mechanism of action is that PUFAs prevent the accumulation of lipids in non-adipocytes. In rodents, fish oil prevented lipid accumulation in adipose tissue more efficiently compared with other dietary oils, and it was suggested that omega-3 PUFAs increase fatty acid oxidation and inhibit triglyceride synthesis through affecting expression of specific genes involved in these metabolic pathways (Jump et al., 1994).

    13.3.3 Regulation of gene expression by polyunsaturated fatty acid

    Fatty acids are converted to fatty acyl coenzyme A (CoA) rapidly after entering a cell. The fatty acid derivatives are then shunted into different cellular pathways such as oxidation for production of energy, membrane synthesis, elongation and/or desaturation, or production of signalling molecules. PUFAs have an important function in regulating gene expression. Several transcription factors such as PPARs, SREBPs, hepatocyte nuclear factor-4a (HNF-4a) and liver X receptors (LXRa) have PUFAs as ligands (Krey et al., 1997; Worgall et al., 1998). The fatty acids bind to PPARs resulting in altered expression of genes involved in fatty acid degradation and oxidation, which in turn leads to reduced intracellular accumulation of triglycerides. Transcription of genes encoding lipogenic enzymes such as fatty acid synthase (FAS), acetyl-CoA carboxylase (ACC), and stearoyl-CoA desaturase (SCD) is down-regulated, while transcription of enzymes involved in fatty acid oxidation such as acyl-CoA oxidase (ACO), medium-chain acyl-CoA dehydrogenase (MCAD), carnitine palmitoyl transferase 1 (CPT-1), acyl- CoA synthase (ACS) and uncoupling protein 2 (UCP-2) is up-regulated (Krey et al., 1997; Nakatani et al., 2003; Levy et al., 2004; Ide, 2005). This leads to pleiotrophic and complex actions of PUFAs involving a large variety of intracellular regulatory pathways. SREBP-1 is another transcription factor that regulates fatty acid metabolism in the liver in that its activation results in increased transcription of genes involved in lipogenesis (Horton et al., 2002). Recent data have shown that rats fed a diet enriched with fish oil had reduced effect and expression of SREBPs in the liver (Xu et al., 2001; Nakatani et al., 2003). The overall effect of PUFAs on gene expression results in accelerated oxidation of fat and reduced lipogenesis.

    13.3.4 The mechanism of polyunsaturated fatty acid in insulin resistance and type 2 diabetes

    The molecular effects of PUFAs are such that these fatty acids may have an impact on the regulation of insulin sensitivity (Lombardo and Chicco, 2006). There are indeed indications that omega-3 PUFAs may have positive effects on glucose tolerance by reducing insulin resistance, as demonstrated in rodent models of obesity (Storlien et al., 2000). Rats fed a high-fat diet supplemented with a low ratio of omega-6: omega-3 PUFA maintained normal insulin action, while rats fed a diet containing high levels of saturated and monounsaturated fats showed insulin resistance in several tissues (Storlien et al., 1991). Feeding fish oil to mice, providing 5–10% of the daily energy intake, accelerated glucose uptake and maintained glucose homeostasis during high-fat feeding (Storlien et al., 1997). The favourable effects of fish oil-derived PUFAs may be explained by suppression of hepatic fatty acids synthesis and increased fat oxidation. Another mechanism behind the positive effects of PUFAs on insulin sensitivity may occur through alteration in the plasma membrane composition of the cells. There is some evidence indicating that altered membrane structure may affect both insulin action and insulin binding to its receptor (Storlien et al., 1996). Another possible mechanism behind the effects of PUFAs in metabolism can be attributed to changes in protein acylation. Many membrane proteins are modified by fatty acid acylation with saturated fatty acids like palmitate or myristate. Whether this has any significant effects in insulin signalling, or whether PUFAs play a role, is unknown at the present time. In summary, the metabolic effects of omega-3 PUFAs promote the reduction of triglyceride in skeletal muscle and liver, which in turn is associated with improved insulin action and glucose tolerance thereby preventing development of insulin resistance.

    13.3.5 Islet metabolism, insulin secretion and polyunsaturated fatty acid

    Besides insulin resistance defective islet function is also of importance for the development of glucose intolerance and type 2 diabetes. In fact, a normal islet function with a normal compensation in insulin secretion is a prerequisite for maintaining normal glucose homeostasis in insulin resistance (Ahren and Pacini, 2005). Therefore, to improve glucose homeostasis, effects on islet function are required. Fatty acids are known to acutely stimulate insulin secretion via several possible pathways. First, it is believed that fatty acids are taken up into the B-cell, where they are converted to long-chain acyl-CoA (LC-CoA). Through glucose metabolism the uptake and oxidation of the fatty acids are blocked through the effect of malonyl- CoA, which accumulates in the cytosol when B-cells are exposed to high glucose concentrations (Corkey et al., 1989, Prentki et al., 1992). Malonyl- CoA is an effective inhibitor of CPT-1, inhibiting the transport of fatty acyl-CoA into the mitochondria, resulting in increased accumulation of LC-CoA in the cytosol. LC-CoA has been found to exert effects at several levels in the B-cell to promote second-phase insulin secretion: through binding to the KATP channels, affecting the exocytosis of insulin granulae, activation of protein kinases via acylation mechanism and thereby promoting insulin secretion (Corkey et al., 2000, Deeney et al., 2000, Yaney et al., 2000). Although this seems to be a common pathway for most of the fatty acids, saturated fats are more potent in stimulating glucose-induced insulin secretion than unsaturated ones, as was recently observed in isolated human islets (Gravena et al., 2002).

    Another pathway for the fatty acids to stimulate insulin secretion is through the fatty acid binding protein GPR40 (Itoh et al., 2003; Salehi et al., 2005; Shapiro et al., 2005). This is a G-protein-coupled receptor that has fatty acids as substrate. Both saturated (C12–C16) and unsaturated (C18–C22) fatty acids have the potency to induce increased intracellular Ca2+ in Chinese hamster ovary (CHO) cells transfected with the GPR40 receptor (Itoh et al., 2003; Itoh and Hinuma, 2005). A third indirect pathway for fatty acids to stimulate insulin secretion is through phospholipase A2 (PLA2), which is activated during glucose stimulation (Simonsson and Ahren, 2000). PLA2 stimulates the formation of arachidonic acid and inhibition of PLA2 results in blunted arachidonic acid formation, which was accompanied by reduced glucose-stimulated insulin secretion. Fish oil has been found to induce insulin secretion through incorporation of the omega-3 PUFAs in the plasma membrane to compete with the production of arachidonic acid.

    In a recent study, inclusion of 7% omega-3 PUFAs in a high-fat diet fed to rats resulted in lower glucose-stimulated insulin secretion from isolated islets, possibly through direct effects of the fatty acids on the islets, blocking the hyper-secretion induced by saturated fatty acids (Holness et al., 2003). In addition, in vivo, PUFA supplementation in rats fed a high-fat diet resulted in reversed insulin hyper-secretion, suggesting that PUFAs may have acute effects on islets resulting in reduced insulin secretion (Holness et al., 2004). Therefore, PUFAs seems to be protective at low doses in fatty acid-induced apoptosis and may have anti-apoptotic effects in islets in vivo. Furthermore, the normalising effect of omega-3 PUFAs on high-fat diet- induced hyperinsulinaemia in response to glucose may have long-term beneficial effects on insulin sensitivity.

    13.3.6 Polyunsaturated fatty acids and inflammation

    It is now recognised that the adipocytes produce and actively secrete many hormones and cytokines into the circulation (Ahima and Flier, 2000). Many of these factors, collectively termed adipokines, are involved in inflammation and it has been suggested that inflammation is one important factor behind the development of obesity-related diseases (Havel, 2004; Berg and Scherer, 2005; Wellen and Hotamisligil, 2005).

    The link between fatty acids and inflammation lies in the fact that the inflammatory mediators termed eicosanoids are generated from long-chain fatty acids. The role of PUFAs in inflammation has recently been thoroughly reviewed (Browning, 2003; Wu, 2004; Calder, 2005). Inflammatory cells contain high levels of the omega-6 PUFA arachidonic acid and low levels of the omega-3 PUFA EPA. The eicosanoids include prostaglandins, thromboxanes and leukotrienes, and these are typically produced from arachidonic acid. The eicosanoids in turn enhance the generation of reactive oxygen species and production of inflammatory cytokines like tumour necrosis factor-1a (TNF-1), interleukin-1 (IL-1) and IL-6 (Calder, 2005). Increased consumption of the omega-3 PUFAs EPA and DHA results in elevated levels of these fatty acids in the inflammatory cells, resulting in reduced production of eicosanoids with arachidonic acid as precursor. The eicosanoids produced from EPA are believed to be less potent in their inflammatory action compared with those formed from arachidonic acid. Thus, one positive effect of omega-3 PUFAs in inflammation is that less-potent eicosanoids are produced. Furthermore, EPA is precursor to a novel group of anti-inflammatory mediators (E-series resolvins) that may be of importance in the mechanism of action of PUFAs in inflammation (Serhan et al., 2002).

    EPA and DHA have a number of other anti-inflammatory effects down-stream of the eicosanoid production. For example in cell culture systems with endothelial cells, EPA and DHA inhibited the production of IL-6 and IL-8 (De Caterina et al., 1994). Dietary supplementation of fish oil in both rodents and humans has resulted in decreased production of TNF-1a, IL-1 and IL-6 (Endres et al., 1989; Yaqoob and Calder, 1995; Caughey et al., 1996). Omega-3 PUFAs may also have a direct effect on inflammatory gene expression through activation of transcription factors such as nuclear factor (NF)-B (Novak et al., 2003). Taken together, long-chain omega-3 PUFAs may function as anti-inflammatory agents in the prevention and/or treatment of obesity and its related diseases.

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    13.4 Producing omega-3 polyunsaturated fatty acids

    13.4.1 Types and sources of polyunsaturated fatty acids

    The therapeutic significance of omega-3 PUFAs has been clearly indicated in clinical trials and epidemiological studies (Bucher et al., 2002; Hu et al., 2002). Fatty fish or fish oils are the richest sources of long-chain omega-3 PUFAs, but as already discussed, the dietary intake of fish has decreased. However, fish stocks are also declining and there have been reports indicating the accumulation of heavy metals and pollutants in some fish (Hites et al., 2004). There is thus an urgent need for alternative sources of long-chain omega-3 PUFAs and there is considerable interest in developing new techniques for this purpose. The primary producers of various omega-3 PUFAs in nature are bacteria, algae, fungi, insects and some invertebrates. Other PUFAs are extracted from oily plant seeds (Table 13.2).

    13.4.2 Production and purification of omega-3 polyunsaturated fatty acids

    The long-chain PUFAs arachidonic acid, EPA and DHA (Fig. 13.1) are of nutritional importance and also play important roles in the prevention of various diseases. Fish oil is the conventional source of EPA and DHA. However, fish oils contain a crude mixture of several different fatty acids and the omega-3 PUFAs need to be extracted and purified before they can be used for dietary supplementation in pharmacological applications. It should be noted that fish cannot produce the long-chain omega-3 PUFAs by themselves and the fatty acids that can be extracted from fish fat derive originally from marine microalgae. Many methods have been used to purify EPA and DHA from fish oil including, for example, chromatographic methods, distillation, enzymatic splitting and crystallisation. However, these processes are expensive and new methods and sources need to be identified. Microalgae produce omega-3 PUFAs and several studies have been performed to develop a commercially feasible technology to produce EPA directly from these marine plants (Wen and Chen, 2003). Even though there are a large number of EPA-containing microalgae, few have demonstrated industrial production potential. The major problems have been low growth rate, low cell density and high cost in the conventional photoautotrophic conditions. An alternative method is a heterotrophic cultivation system, where an organic carbon source such as sugar can be used as the sole energy source. This mode of culture eliminates the requirement for light and may increase productivity (Wen and Chen, 2003).

    Recent progress has been made using another approach to produce long-chain PUFAs, which involves the use of transgenic plants (Napier et al., 2004, Qi et al., 2004). Long-chain omega-3 PUFAs such as arachidonic acid and EPA were produced and accumulated in plants that had been transfected with genes encoding enzymes participating in the omega-3/omega-6 biosynthetic pathway for formation of long-chain PUFAs. This is a new promising method for alternative production of these essential fatty acids.

    13.5 Omega-3 and other polyunsaturated fatty acids in functional food products

    Functional foods are food products that have beneficial effects on physiology and/or have the ability to reduce the risk of a disease. Functional foods may be conventional food or foods that have been enriched with functional components to provide greater health benefits, but they do not include purified substances provided in pills or capsules. Since omega-3 PUFAs have been shown to have beneficial effects in several health conditions they are considered to be a functional food. The positive effects of omega-3 PUFAs in different diseases have been established and these fatty acids have been particularly interesting in coronary heart disease but also in several other conditions such as arteriosclerosis, type 2 diabetes, cancer, depression and asthma (de Lorgeril et al., 1994; Simopoulos, 1999; Ruxton et al., 2004; Nettleton and Katz, 2005). The beneficial effects of omega-3 PUFAs on health have resulted in the production of dietary supplements becoming a large industry. There is also a large and growing market for producing functional foods enriched in omega-3 PUFAs, such as omega-3-enriched eggs or omega-3 PUFA-supplemented margarine. For example, in Sweden a dairy product company has produced a margarine containing 40% fat and consisting of butter, rapeseed oil and fish oil. Several companies have specialised in extracting omega-3 PUFAs from fish to provide omega-3-enriched fish oil to be used for the production of functional foods. Fish oil was earlier considered difficult to include in cooking or as a supplement in foods since it has a peculiar smell and taste. However, with today’s techniques it is possible to produce fish oil extracts without this problem, making it easier to produce food products enriched with these fatty acids.

    13.6 Future trends

    13.6.1 Dietary recommendations and therapeutic use

    As presented here, PUFAs have the potential to affect a large number of metabolic processes and, therefore, these fatty acids are beneficial in obesity and its related diseases. The most important effect of omega-3 PUFAs, and in particular EPA and DHA, is the triglyceride-lowering effect observed in humans (Connor et al., 1993). Lowering circulating triglycerides has been proven to protect against coronary heart disease and the use of fish oil or increased consumption of fish after myocardial infarction reduced reinfarction and mortality (Calder, 2004). The American Heart Association have presented guidelines for dietary fish intake, proposing that patients without documented coronary heart disease should eat a variety of fish, preferably oily fish, twice a week (Kris-Etherton et al., 2002). Patients with documented coronary heart disease should consume dietary supplementation of at least 1g EPA and DHA per day. Long-chain omega-3 PUFAs derived from fish and fish oils have beneficial effects in people with pre-existing cardiovascular heart disease. One serving of fish per week may decrease the risk of mortality in heart failure by up to 40%. Patients with type 2 diabetes are often overweight or obese. To better control this disease it is important to eat healthily and to control fat intake. The American Diabetes Association recommend two to three servings of fish per week and the use of vegetable oils instead of butter in cooking (American Diabetes Association Home Page). Furthermore, the Department of Health and Human Services (HHS) and the Department of Agriculture (USDA) publish annually the Dietary Guidelines for Americans (Dietary Guidelines for Americans) providing advice on good dietary habits, which can promote health and reduce risk for major chronic diseases.

    The role of PUFAs for body weight control is, however, at the present time not fully understood. Most studies indicate no change in body weight after increased intake of PUFAs. However, incorporation of a fish meal in a weight-loss programme improved the response to the diet with a tendency to increased weight loss, although this was not statistically significant (Mori et al., 1999). Fasting insulin levels were significantly reduced and the lipid profile improved with decreased triglyceride levels and increased high-density lipoprotein levels. A dietary recommendation that is valid for all individuals is to consume a diet with: (1) decreased total fat content; (2) reduced saturated fat content; (3) reduced omega-6 : omega-3 fatty acid ratio by increasing the intake of omega-3 PUFAs. This would be recommended to maintain body weight and whole-body glucose and lipid metabolism.

    The positive effects of fish oil and omega-3 PUFAs in cardiovascular disease and mortality are apparent. However, most studies with increased fish intake or addition of dietary fish oil supplementation do not take into account that there may be other components present in fish that may be important in cardiovascular health. The recommendation by the American Heart Association is that the degree of PUFAs in the diet should be increased and that the ratio of omega-6 : omega-3 PUFAs needs to be reduced. This will be achieved by increased consumption of plant-derived a-linolenic acid and marine-derived EPA and DHA (Kris-Etherton et al., 2002). Another source of essential omega-3 PUFAs is walnuts, which despite being energy dense have no implications in inducing altered energy balance. Hence, incorporation of nuts into diets with low levels of saturated fats may have beneficial effects on weight reduction and maintenance (Gillen et al., 2005).

    In summary, different fat types have different effects on satiety. To be able to make clear recommendations regarding dietary PUFA supplementation, more studies are needed to evaluate the correct composition of fatty acids that induces satiety and maintains energy balance. Methods for prevention of metabolic abnormalities such as overweight, obesity and type 2 diabetes are urgently required and a primary long-term strategy to cure these diseases is to improve dietary habits. The use of PUFAs in the diet may, by stimulating the use of fat as an energy substrate and by reducing the accumulation of fat in the adipose tissue, significantly contribute to the maintenance or reduction of body weight.


    This work has been supported by the Swedish Research Council (grant 6834), the European Union (grant QLK6-2002-02288, OB-AGE), the Swedish Diabetes Association, Region Skåne and the Faculty of Medicine, Lund University.

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  10. Very interesting post as usual datBtrue. I haven't been able to read through all of it yet but what I did was very interesting. Can't wait to see the rest.

  11. Do you have any specific numbers as to the ratio of EPA/DHA. Different fish oil supplements have different ratios and mg's included.

    I may have missed any specific reference to it, if you know what post # its in i can read it for myself, thanks.


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