An Increase in the Omega-6/Omega-3 Fatty Acid Ratio Increases the Risk for Obesity

Hamazaki, 2001, Evolutionary aspects of diet and essential fatty acids, Fatty Acids and Lipids—New Findings, Volume 88, 18

Simopoulos, 2003, The importance of omega-6/omega-3 fatty acid ratio in cell function. The gene transfer of omega-3 fatty acid desaturase, Omega-6/Omega-3 Essential Fatty Acid Ratio: The Scientific Evidence, Volume 92, 23, 10.1159/000073790

Simopoulos, 2008, The importance of the omega-6/omega-3 Fatty Acid ratio in cardiovascular disease and other chronic diseases, Exp. Biol. Med., 233, 674, 10.3181/0711-MR-311

Simopoulos, 2013, Dietary Omega-3 Fatty Acid Deficiency and High Fructose Intake in the Development of Metabolic Syndrome, Brain Metabolic Abnormalities, and Non-Alcoholic Fatty Liver Disease, Nutrients, 5, 2901, 10.3390/nu5082901

Donahue, 2011, Prenatal fatty acid status and child adiposity at age 3 years: Results from a US pregnancy cohort, Am. J. Clin. Nutr., 93, 780, 10.3945/ajcn.110.005801

Kromhout, 2014, Update on cardiometabolic health effects of ω-3 fatty acids, Curr. Opin. Lipidol., 25, 85, 10.1097/MOL.0000000000000041

Kromann, 1980, Epidemiological studies in the Upernavik district, Greenland. Incidence of some chronic diseases 1950–1974, Acta Med. Scand., 208, 401, 10.1111/j.0954-6820.1980.tb01221.x

Adler, 1994, Lower prevalence of impaired glucose tolerance and diabetes associated with daily seal oil or salmon consumption among Alaska Natives, Diabetes Care, 17, 1498, 10.2337/diacare.17.12.1498

Schraer, 1999, Low fasting insulin levels in Eskimos compared to American Indians: are Eskimos less insulin resistant?, Int. J. Circumpolar Health, 58, 272

Nettleton, 2005, n-3 long-chain polyunsaturated fatty acids in type 2 diabetes: A review, J. Am. Diet. Assoc., 105, 428, 10.1016/j.jada.2004.11.029

Mozaffarian, 2006, Fish intake, contaminants, and human health: Evaluating the risks and the benefits, JAMA, 296, 1885, 10.1001/jama.296.15.1885

Birch, 2002, A randomized controlled trial of long-chain polyunsaturated fatty acid supplementation of formula in term infants after weaning at 6 wk of age, Am. J. Clin. Nutr., 75, 570, 10.1093/ajcn/75.3.570

Guesnet, 1999, Blood lipid concenttrations of docosahexaenoic and arachidonic acids at birth determine their relative postnatal changes in term infants fed breast milk or formula, Am. J. Clin. Nutr., 70, 292, 10.1093/ajcn.70.2.292

Couet, 1997, Effect of dietary fish oil on body fat mass and basal fat oxidation in healthy adults, Int. J. Obes. Relat. Metab. Disord., 21, 637, 10.1038/sj.ijo.0800451

Fontani, 2005, Blood profiles, body fat and mood state in healthy subjects on different diets supplemented with omega-3 polyunsaturated fatty acids, Eur. J. Clin. Investig., 35, 499, 10.1111/j.1365-2362.2005.01540.x

Hill, 2007, Combining fish-oil supplements with regular aerobic exercise improves body composition and cardiovascular disease risk factors, Am. J. Clin. Nutr., 85, 1267, 10.1093/ajcn/85.5.1267

Belury, 2003, The conjugated linoleic acid (CLA) isomer, t10c12-CLA, is inversely associated with changes in body weight and serum leptin in subjects with type 2 diabetes mellitus, J. Nutr., 133, 257S, 10.1093/jn/133.1.257S

Chan, 2006, Factorial study of the effect of n-3 fatty acid supplementation and atorvastatin on the kinetics of HDL apolipoproteins A-I and A-II in men with abdominal obesity, Am. J. Clin. Nutr., 84, 37, 10.1093/ajcn/84.1.37

Simopoulos, 2015, The Impact of the Bellagio Report on Healthy Agriculture, Healthy Nutrition, Healthy People: Scientific and Policy Aspects and the International Network of Centers for Genetics, Nutrition and Fitness for Health, J. Nutrigenet. Nutrigenom., 7, 189

Simopoulos, 1991, ω-3 fatty acids in health and disease and in growth and development, Am. J. Clin. Nutr., 54, 438, 10.1093/ajcn/54.3.438

Brenner, 1975, Oxidative desaturation of alphalinolenic, linoleic, and stearic acids by human liver microsomes, Lipids, 10, 315, 10.1007/BF02532451

Baillie, T.A., and Jones, J.R. (1989). Synthesis and Application of Isotopically Labeled Compounds 1988, Elsevier Science Publishers.

Hague, 1984, Effect of dietary fats on arachidonic acid and eicosapentaenoic acid biosynthesis and conversion to C22 fatty acids in isolated liver cells, Biochim. Biophys. Acta, 796, 205, 10.1016/0005-2760(84)90349-7

Hague, 1986, Evidence for peroxisomal retroconversion of adrenic acid (22, 4n6) and docosahexaenoic acid (22, 6n3) in isolated liver cells, Biochim. Biophys. Acta, 875, 165, 10.1016/0005-2760(86)90165-7

Indu, 1992, N-3 fatty acids in Indian diets—Comparison of the effects of precursor (alpha-linolenic acid) vs. product (long chain n-3 polyunsaturated fatty acids), Nutr. Res., 12, 569, 10.1016/S0271-5317(05)80027-2

Ameur, 2012, Genetic Adaptation of Fatty-Acid Metabolism: A Human-Specific Haplotype Increasing the Biosynthesis of Long-Chain ω-3 and ω-6 Fatty Acids, Am. J. Hum. Genet., 90, 809, 10.1016/j.ajhg.2012.03.014

Sergeant, 2012, Differences in arachidonic acid levels and fatty acid desaturase (FADS) gene variants in African Americans and European Americans with diabetes or the metabolic syndrome, Br. J. Nutr., 107, 547, 10.1017/S0007114511003230

Mathias, 2011, The impact of FADS genetic variants on ω6 polyunsaturated fatty acid metabolism in African Americans, BMC Genet., 12, 50, 10.1186/1471-2156-12-50

Carlson, 1986, Docosahexaenoic acid status of preterm infants at birth and following feeding with human milk or formula, Am. J. Clin. Nutr., 44, 798, 10.1093/ajcn/44.6.798

Singer, 1984, Defective desaturation and elongation of n-6 and n-3 fatty acids in hypertensive patients, Prostaglandins Leukot. Med., 15, 159, 10.1016/0262-1746(84)90173-2

Honigmann, 1982, Influence of a diet rich in linolenic acid on lipids, thrombocyte aggregation and prostaglandins in type I (insulin-dependent) diabetes, Diabetologia, 23, 175

Simopoulos, 1999, Essential fatty acids in health and chronic disease, Am. J. Clin. Nutr., 70, 560S, 10.1093/ajcn/70.3.560s

Simopoulos, 2011, The importance of the ω-6/ω-3 Balance in Health and Disease: Evolutionary Aspects of Diet, Healthy Agriculture, Healthy Nutrition, Healthy People, Volume 102, 10, 10.1159/000327785

Eaton, 1985, Paleolithic nutrition. A consideration of its nature and current implications, N. Engl. J. Med., 312, 283, 10.1056/NEJM198501313120505

Simopoulos, 1998, Overview of evolutionary aspects of ω3 fatty acids in the diet, The Return of ω-3 Fatty Acids into the Food Supply. I. Land-Based Animal Food Products and Their Health Effects, Volume 83, 1

Crawford, 1968, Fatty acid ratios in free-living and domestic animals, Lancet, 1, 1329, 10.1016/S0140-6736(68)92034-5

Wo, 1975, Vitamin E status of Alaskan Eskimos, Am. J. Clin. Nutr., 28, 808, 10.1093/ajcn/28.8.808

Crawford, 1969, Linoleic acid and linoleic acid elongation products in muscle tissue of Syncerus caffer and other ruminant species, Biochem. J., 115, 25, 10.1042/bj1150025

Raper, 1992, ω-3 fatty acid content of the US food supply, J. Am. College Nutr., 11, 304, 10.1080/07315724.1992.10718231

Simopoulos, 1986, Purslane: A terrestrial source of ω-3 fatty acids, N. Engl. J. Med., 315, 833, 10.1056/NEJM198609253151313

Katan, 1990, Lower ratio of n-3 to n-6 fatty acids in cultured than in wild fish, Am. J. Clin. Nutr., 51, l

Simopoulos, 1992, Egg yolk as a source of long-chain polyunsaturated fatty acids in infant feeding, Am. J. Clin. Nutr., 55, 411, 10.1093/ajcn/55.2.411

Simopoulos, 1992, Common purslane: A source of ω-3 fatty acids and antioxidants, J. Am. Coll. Nutr., 11, 374, 10.1080/07315724.1992.10718240

Simopoulos, 1989, Nutrition and Fitness, JAMA, 261, 2862, 10.1001/jama.1989.03420190138045

Simopoulos, 1989, N-3 Fatty acid in eggs from range-fed Greek chickens, N. Engl. J. Med., 321, 1412, 10.1056/NEJM198911163212013

Simopoulos, 1995, Purlsane in human nutrition and its potential for world agriculture, Plants in Human Nutrition, Volume 77, 47, 10.1159/000424465

Spiller, G.A. (1995). Handbook of Lipids in Human Nutrition, CRC Press.

Dupont, 1991, Saturated and hydrogenated fats in food in relation to health, J. Am. Coll. Nutr., 10, 577, 10.1080/07315724.1991.10718180

Litin, 1993, Trans-fatty acid content of common foods, N. Engl. J. Med., 329, 1969, 10.1056/NEJM199312233292621

Guil, 1996, Identification of fatty acids in edible wild plants by gas chromatography, J. Chromatogr. A, 719, 229, 10.1016/0021-9673(95)00414-9

Cordain, 1998, The fatty acid composition of muscle, brain, marrow and adipose tissue in elk: Evolutionary implications for human dietary lipid requirements, World Rev. Nutr. Diet., 83, 225

Sinclair, 1982, The analysis of polyunsaturated fatty acids in meat by capillary gas-liquid chromatography, J. Food Sci. Agri., 33, 771, 10.1002/jsfa.2740330814

Simopoulos, 1996, The role of fatty acids in gene expression: Health implications, Ann. Nutr. Metab., 40, 303, 10.1159/000177929

Elton, S., and O’Higgins, P. (2008). Medicine and Evolution: Current Applications, Future Prospects, CRC Press.

Eaton, 1988, Stone agers in the fast lane: Chronic degenerative diseases in evolutionary perspective, Am. J. Med., 84, 739, 10.1016/0002-9343(88)90113-1

Kuipers, 2010, Estimated macronutrient and fatty acid intakes from an East African Paleolithic diet, Br. J. Nutr., 104, 1666, 10.1017/S0007114510002679

Guil-Guerrero, J.L., Tikhonov, A., Rodríguez-García, I., Protopopov, A., Grigoriev, S., and Ramos-Bueno, R.P. (2014). The fat from frozen mammals reveals sources of essential fatty acids suitable for Palaeolithic and Neolithic humans. PLoS ONE, 9.

Simopoulos, 1998, Dietary intake of long-chain polyunsaturated fatty acids during the Paleolithic, The Return of w-3 Fatty Acids into the Food Supply. I. Land-Based Animal Food Products and Their Health Effects, Volume 83, 12

Simopoulos, 2003, Importance of the ratio of ω-6/ω-3 essential fatty acids: Evolutionary aspects, Omega-6/Omega-3 Essential Fatty Acid Ratio: The Scientific Evidence, Volume 92, 1, 10.1159/000073788

Amri, 1994, Fatty acids as signal transducing molecules: Involvement in the differentiation of preadipose to adipose cells, J. Lipid Res., 35, 930, 10.1016/S0022-2275(20)39187-2

Jump, 1994, Coordinate regulation of glycolytic and lipogenic gene expression by polyunsaturated fatty acids, J. Lipid Res., 35, 1076, 10.1016/S0022-2275(20)40103-8

Clarke, 1997, Polyunsaturated fatty acids regulate lipogenic and peroxisomal gene expression by independent mechanisms, Prostaglandins Leukot. Essent. Fatty Acids, 57, 65, 10.1016/S0952-3278(97)90494-4

Schwinkendorf, 2011, Effects of central administration of distinct fatty acids on hypothalamic neuropeptide expression and energy metabolism, Int. J. Obes., 35, 336, 10.1038/ijo.2010.159

James, 2000, Dietary polyunsaturated fatty acids and inflammatory mediator production, Am. J. Clin. Nutr., 71, 343S, 10.1093/ajcn/71.1.343S

Gaillard, 1989, Requirement and role of arachidonic acid in the differentiation of preadipose cells, Biochem. J., 257, 389, 10.1042/bj2570389

Corey, 1983, Docosahexaenoic acid is a strong inhibitor of prostaglandin but not leukotriene biosynthesis, Proc. Natl. Acad. Sci. USA, 80, 3581, 10.1073/pnas.80.12.3581

Massaro, 2006, The omega-3 fatty acid docosahexaenoate attenuates endothelial cyclooxygenase-2 induction through both NADP(H) oxidase and PKC epsilon inhibition, Proc. Natl. Acad. Sci. USA, 103, 15184, 10.1073/pnas.0510086103

Ringbom, 2001, Cox-2 inhibitory effects of naturally occurring and modified fatty acids, J. Nat. Prod., 64, 745, 10.1021/np000620d

Mirnikjoo, 2001, Protein kinase inhibition by omega-3 fatty acids, J. Biol. Chem., 276, 10888, 10.1074/jbc.M008150200

Hennig, 1989, Linoleic acid and linolenic acid: Effect on permeability properties of cultured endothelial cell monolayers, Am. J. Clin. Nutr., 49, 301, 10.1093/ajcn/49.2.301

Ukropec, 2003, The hypotriglyceridemic effect of dietary n-3 FA is associated with increased beta-oxidation and reduced leptin expression, Lipids, 38, 1023, 10.1007/s11745-006-1156-z

Lepperdinger, 2011, Inflammation and mesenchymal stem cell aging, Curr. Opin. Immunol., 23, 518, 10.1016/j.coi.2011.05.007

Massiera, 2010, A Western-like fat diet is sufficient to induce a gradual enhancement in fat mass over generations, J. Lipid Res., 51, 2352, 10.1194/jlr.M006866

Pisani, 2015, Disequilibrium of polyunsaturated fatty acids status and its dual effect in modulating adipose tissue development and functions, OCL, 22, D405, 10.1051/ocl/2015003

Baillie, 1999, Coordinate induction of peroxisomal acyl-CoA oxidase and UCP-3 by dietary fish oil: A mechanism for decreased body fat deposition, Prostaglandins Leukot. Essent. Fatty Acids, 60, 351, 10.1016/S0952-3278(99)80011-8

Phillips, 2010, Leptin receptor polymorphisms interact with polyunsaturated fatty acids to augment risk of insulin resistance and metabolic syndrome in adults, J. Nutr., 140, 238, 10.3945/jn.109.115329

Cheng, 2015, Arachidonic acid impairs hypothalamic leptin signaling and hepatic energy homeostasis in mice, Mol. Cell. Endocrinol., 5, 412, 12, 10.1016/j.mce.2015.04.025

Martinez, 2007, Eicosapentaenoic acid actions on adiposity and insulin resistance in control and high-fat-fed rats: Role of apoptosis, adiponectin and tumour necrosis factor-alpha, Br. J. Nutr., 97, 389, 10.1017/S0007114507207627

Hassanali, 2010, Dietary supplementation of n-3 PUFA reduces weight gain and improves postprandial lipaemia and the associated inflammatory response in the obese JCR: LA-cp rat, Diabetes Obes. Metab., 12, 139, 10.1111/j.1463-1326.2009.01130.x

Alvheim, 2014, Dietary linoleic acid elevates the endocannabinoids 2-AG and anandamide and promotes weight gain in mice fed a low fat diet, Lipids, 49, 59, 10.1007/s11745-013-3842-y

Banni, 2010, Effect of dietary fat on endocannabinoids and related mediators: consequences on energy homeostasis, inflammation and mood, Mol. Nutr. Food Res., 54, 82, 10.1002/mnfr.200900516

Matias, 2007, Endocannabinoids and the control of energy balance, Trends Endocrinol. Metab., 18, 27, 10.1016/j.tem.2006.11.006

Buckley, 2009, Anti-obesity effects of long-chain omega-3 polyunsaturated fatty acids, Obes. Rev., 10, 648, 10.1111/j.1467-789X.2009.00584.x

Hainault, 1993, Fish oil in a high lard diet prevents obesity, hyperlipemia, and adipocyte insulin resistance in rats, Ann. N. Y. Acad. Sci., 683, 98, 10.1111/j.1749-6632.1993.tb35696.x

Belzung, 1993, Fish oil n-3 fatty acids selectively limit the hypertrophy of abdominal fat depots in growing rats fed high-fat diets, Am. J. Physiol., 264, R1111

Parrish, 1990, Dietary fish oils limit adipose tissue hypertrophy in rats, Metabolism, 39, 217, 10.1016/0026-0495(90)90038-E

Ruzickova, 2004, Omega-3 PUFA of marine origin limit diet-induced obesity in mice by reducing cellularity of adipose tissue, Lipids, 39, 1177, 10.1007/s11745-004-1345-9

Nuernberg, 2011, Metabolic responses to high-fat diets rich in n-3 or n-6 long-chain polyunsaturated fatty acids in mice selected for either high body weight or leanness explain different health outcomes, Nutr. Metab., 8, 56, 10.1186/1743-7075-8-56

Kang, 2004, Transgenic mice: Fat-1 mice convert n-6 to n-3 fatty acids, Nature, 427, 504, 10.1038/427504a

Jump, 1999, Regulation of gene expression by dietary fat, Annu. Rev. Nutr., 19, 63, 10.1146/annurev.nutr.19.1.63

Jump, 2002, Dietary polyunsaturated fatty acids and regulation of gene transcription, Curr. Opin. Lipidol., 13, 155, 10.1097/00041433-200204000-00007

Suzukawa, 1995, Effects of fish oil fatty acids on low-density lipoprotein size, oxidizability, and uptake by macrophages, J. Lipid Res., 36, 473, 10.1016/S0022-2275(20)39881-3

Li, 2014, Endogenous ω-3 Polyunsaturated Fatty Acid Production Confers Resistance to Obesity, Dyslipidemia, and Diabetes in Mice, Mol. Endocrinol., 28, 1316, 10.1210/me.2014-1011

Kabir, 2007, Treatment for 2 mo with n 3 polyunsaturated fatty acids reduces adiposity and some atherogenic factors but does not improve insulin sensitivity in women with type 2 diabetes: A randomized controlled study, Am. J. Clin. Nutr., 86, 1670, 10.1093/ajcn/86.5.1670

Thorsdottir, 2007, Randomized trial of weight-loss-diets for young adults varying in fish and fish oil content, Int. J. Obes., 31, 1560, 10.1038/sj.ijo.0803643

Parra, 2008, A diet rich in long chain omega-3 fatty acids modulates satiety in overweight and obese volunteers during weight loss, Appetite, 51, 676, 10.1016/j.appet.2008.06.003

Krebs, 2006, Additive benefits of long-chain n-3 polyunsaturated fatty acids and weight-loss in the management of cardiovascular disease risk in overweight hyperinsulinaemic women, Int. J. Obes., 30, 1535, 10.1038/sj.ijo.0803309

Kunesova, 2006, The influence of n-3 polyunsaturated fatty acids and very low calorie diet during a short-term weight reducing regimen on weight loss and serum fatty acid composition in severely obese women, Physiol. Res., 55, 63, 10.33549/physiolres.930770

Simopoulos, 2010, Genetic variants in the metabolism of omega-6 and omega-3 fatty acids: their role in the determination of nutritional requirements and chronic disease risk, Exp. Biol. Med., 235, 785, 10.1258/ebm.2010.009298

Wang, L., Manson, J.E., Rautiainen, S., Gaziano, J.M., Buring, J.E., Tsai, M.Y., and Sesso, H.D. (2015). A prospective study of erythrocyte polyunsaturated fatty acid, weight gain, and risk of becoming overweight or obese in middle‑aged and older women. Eur. J. Nutr.

Claussnitzer, 2015, FTO Obesity Variant Circuitry and Adipocyte Browning in Humans, N. Engl. J. Med., 373, 895, 10.1056/NEJMoa1502214

Savva, 2004, Association of adipose tissue arachidonic acid content with BMI and overweight status in children from Cyprus and Crete, Br. J. Nutr., 91, 643, 10.1079/BJN20031084

Jensen, 1997, Effect of dietary linoleic/alpha-linolenic acid ratio on growth and visual function of term infants, J. Pediatr., 131, 200, 10.1016/S0022-3476(97)70154-9

Ahima, 2008, Brain regulation of appetite and satiety, Endocrinol. Metab. Clin. N. Am., 37, 811, 10.1016/j.ecl.2008.08.005

Artmann, 2008, Influence of dietary fatty acids on endocannabinoid and N-acylethanolamine levels in rat brain, liver and small intestine, Biochim. Biophys. Acta, 1781, 200, 10.1016/j.bbalip.2008.01.006

Yoshida, 2010, Endocannabinoids selectively enhance sweet taste, Proc. Natl. Acad. Sci. USA, 107, 935, 10.1073/pnas.0912048107

Despres, 2008, Efficacy and safety of rimonabant for improvement of multiple cardiometabolic risk factors in overweight/obese patients: Pooled 1-year data from the Rimonabant in Obesity (RIO) program, Diabetes Care, 31, S229, 10.2337/dc08-s258

Christensen, 2007, Efficacy and safety of the weight-loss drug rimonabant: a meta-analysis of randomised trials, Lancet, 370, 1706, 10.1016/S0140-6736(07)61721-8