Obesity: The Pandemic Where You Can't Afford to Capsize the Boat

Booth FW, Laye MJ. Lack of adequate appreciation of physical exercise's complexities can pre-empt appropriate design and interpretation in scientific discovery. J Physiol. 2009;587:5527–5539.

But if we are to delve into the details of obesity, there are two dichotomous factors, which are at play. As I mentioned, too much sugar is a cornerstone of our nation’s various health problems. The fructose transporter GLUT5 plays a specific role in this problem, since we are taking in far too much fructose in our collective diet.^{60 61 62 63 64} By contrast, if we were to eat more vegetables and other healthful foods, we would see better results via the Nrf2 pathway.^{65 66 67 68 69 70} Most of us are aware that free radicals are categorized as ‘bad’ and antioxidants as ‘good’.⁷¹ But the details behind these scientific terms remain elusive, for most of the population.

Evolution of the consumption of high-fructose corn syrup (HFCS) and sucrose in the United States between 1970 and present. HFCS has increased rapidly to replace 50% of the sucrose consumption. Over this period, not only total sugar consumption but also total calorie intake and total fat intake have increased significantly. (USDA)]

Fructose metabolism in liver cells. Fructose metabolism (grey arrows) differs from glucose (black arrows) due to 1) a nearly complete hepatic extraction and 2) different enzyme and reactions for its initial metabolic steps. Fructose taken up by the liver can be oxidized to CO2 and then converted into lactate and glucose; glucose and lactate are subsequently either released into the circulation for extrahepatic metabolism or converted into hepatic glycogen or fat. The massive uptake and phosphorylation of fructose in the liver can lead to a large degradation of ATP to AMP and uric acid.⁶⁰

Summary of the potential mechanisms for fructose-induced insulin resistance.⁶⁰

The research on fructose has been steamrolling the scientific community since the viral popularity of pediatric endocrinologist Robert Lustig’s lecture, a few years ago.^{72 73 74 75} Not surprisingly, the food and beverage industry is trying like mad to stop any bad publicity from arising from the scientific community, around their sugary cash cow.⁷⁶ But the actual, unbiased data has been very damning.^{77 78 79 80} Take the following chart, which shows that fructose in beverages, which do not list it on the label, often contain quantities of fructose that surpass the amount of the substance in beverages which do list it on the label.

Fructose concentration and fructose-to-glucose (F:G) ratio: juices. Concentration of fructose (g/L) in juices is displayed on the left y axis (open bars) and the F:GAdjusted is shown on the right y axis (solid bars). * Products with high-fructose corn syrup listed as an ingredient on the label. F:GAdjusted, the F:G ratio adjusted for other detected disaccharides.

Walker, R.W.; Dumke, K.A.; Goran, M.I. Fructose content in popular beverages made with and without high-fructose corn syrup. Nutrition 2014, 30, 928–935. In an evolutionary sense, this level of fructose consumption is out of control and unprecedented.^{81 82 83} We’ve known for thousands of years, humans consumed about 20g of fructose each day.^{84 85} Their intake came from fruit and honey,⁸⁶ vastly different than more concentrated sources of fructose, like soda. For one thing – there is no fiber in soda, which might slow down hepatic absorption of fructose. Oh, and for those curious, we are now consuming about 80g of fructose per day, on average.^{87 88}

Proposed pathways and mechanisms underlying the differential effects of fructose compared with glucose consumption on adipose deposition, postprandial lipid metabolism glucose tolerance/insulin sensitivity.

Stanhope, K. L., & Havel, P. J. (2010). Fructose consumption: Recent results and their potential implications. Annals of the New York Academy of Sciences, 1190, 15–24. doi:10.1111/j.1749-6632.2009.05266.x

But why is fructose so harmful, and how does the GLUT5 transporter factor into this issue? GLUT5 was successfully cloned around 20 years ago and was initially described as a glucose transporter, until it became clear that it was specifically related to fructose.⁸⁹ The brain and kidneys have both shown levels of GLUT5 mRNA and/or protein.⁹⁰ This (indirectly) means that by eating too much fructose, your brain processes might be impaired.^{91 92 93} Since we now know that high levels of HA1c correlate with dementia, this shouldn’t be shocking news.⁹⁴

Your small intestine has the greatest amount of GLUT5, and it also controls the availability of fructose to other areas.⁹⁵ Interestingly, intestinal GLUT5 mRNA levels and fructose transport rates are very low until fructose is introduced, or after a few weeks of development (this appears to be genomic).^{96 97 98 99} The problems start to arise when too much fructose is introduced (via processed foods, usually) too early, creating a baseline of consumption, which seems to need to be satisfied.^{100 101 102 103} Though the science is still out, this ‘created need’ may force children to overeat, and as a result, become overweight and/or obese.

The GLUT5 transporter has been linked to hypertension, and also to diabetes.^{104 105} Since the United States spends over $240 billion on diabetes annually, scientific research into the area of GLUT5 should be pushed to the forefront, with the hope being that by better understanding the transport and processing of fructose, we can help improve the rates of disease - if not prevent them entirely.¹⁰⁶

For example, diabetes profoundly affects GLUT5 expression in the small intestine.¹⁰⁷ By down-regulating GLUT5 protein levels in those with high blood sugar, we may have a mechanism to help diabetics. Of course, there are many potential areas of research, which could be interesting for the GLUT5 transporter. But for the brevity of this article, I will stop here. I invite those further interested to research the GLUT5 transporter, via easily using a search engine to locate articles on PubMed relating to the topic.

Lustig RH. Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc. 2010;110(9):1307-21.

One of the many issues with fructose is that it helps to cause non-enzymatic glycation – in layman’s terms; fructose helps to age your liver.¹⁰⁸ This shouldn’t be surprising. Remember – increased dietary intake of sugar was linked to dementia – premature aging/degradation of brain tissue usually due to excessive buildup of the beta amyloid protein.¹⁰⁹

By contrast, activation of the Nrf2 pathway may help to stop aging – not just in your liver, but also throughout the body.¹¹⁰ The Nrf2 pathway helps in regulating over 500 cytoprotective genes, which give your cells multiple layers of protection.^{111 112} Interestingly, research has found that dietary flavonoids help to activate this pathway, and thus, your diet can truly determine whether you age quickly or slowly.¹¹³ It really is this simple. Sort of.

NRF2, p53 and FOXOs support complementary antioxidant pathways.

Gorrini, C., Harris, I. S. & Mak, T. W. Modulation of oxidative stress as an anticancer strategy. Nature Rev. Drug Discov. 12, 931–947 (2013).

You see, in science, one must resist the urge to oversimplify, and in this case we must remember to not forget all the other stressors to our cells. This means sleep quantity and quality, exercise, stress from work, genetics, epigenetics, pollution – it is truly a never ending list. However, we very much have control over what we put in our mouths.

Differential responses to rising oxidative stress.

Stefanson, A. L., & Bakovic, M. (2014). Dietary Regulation of Keap1/Nrf2/ARE Pathway: Focus on Plant-Derived Compounds and Trace Minerals. Nutrients, 6(9), 3777–3801. doi:10.3390/nu6093777

The Nrf2 pathway has been recently found to react to apigenin and luteolin (dietary phytochemical flavones) in a favorable way.¹¹⁴ The antioxidant pathway is activated upon ingestion of apigenin and luteolin, and the flavones may be responsible for vital anti-inflammatory effects.

Schematic representation depicting some of the various cytoprotective proteins that are upregulated by Nrf2. Flavonoid-mediated protection from ischemic/hemorrhagic stroke, traumatic brain injury, and/or other neuropathies may result in large part from Nrf2 regulation of these pathways.¹¹³

In fact, activation of the Nrf2 pathway is being studied fairly extensively, in regards to cancer prevention and treatment.¹¹⁵ Since dietary activation is very cheap (especially when compared to pharmaceutical drugs) this research could pave the way for widespread effective change in our world’s health. Mandatory spinach and kale consumption might be a potential guideline - if one was to hypothesize about potential ways this research could be implemented on a widespread basis.

Schematic representation depicting the potential mechanisms by which flavanol-mediated Nrf2 induction leads to activation of cytoprotective pathways after stroke, traumatic brain injury, and/or other neurodegenerative diseases. Flavanols may induce Nrf2 through binding to receptors seated on the plasma membrane and subsequent initiation of intracellular signaling cascades. Alternatively, passive diffusion or active transport through the plasma membrane may permit direct cytosolic dissociation of the Keap1/Nrf2 complex or activation of second messengers that regulate Nrf2 translocation into the nucleus. Upon nuclear translocation, Nrf2 binds to AREs on the promoter regions of cytoprotective genes to regulate heme/biliverdin, glutathione, NAD(P)H, and/or other protective pathways.¹¹³

So, if your diet is making you fat, old and sick, you now have some great motivation to affect change. What can be more powerful than that? By loading up on neuro-protective vegetables and healthy fats, as well as quality proteins (which contain essential amino acids) you will be helping to fight back against cellular aging, obesity and illness.

And good news – a Paleo Diet – by its very nature – eliminates all the bad choices for you, and emphasizes all the best foods. The work has already been done. It couldn’t get any easier. You have a path towards obesity, dementia and medication. You also have a path towards health, wellness and vitality. The choice is yours – so choose wisely.

References

1 Available at: //www.cdc.gov/nchs/fastats/obesity-overweight.htm. Accessed August 26, 2015.

2 Available at: //www.cdc.gov/nchs/data/databriefs/db56. Accessed August 26, 2015.

3 Roth J, Qiang X, Marbán SL, Redelt H, Lowell BC. The obesity pandemic: where have we been and where are we going?. Obes Res. 2004;12 Suppl 2:88S-101S.

4 Swinburn BA, Sacks G, Hall KD, et al. The global obesity pandemic: shaped by global drivers and local environments. Lancet. 2011;378(9793):804-14.

5 Catenacci VA, Hill JO, Wyatt HR. The obesity epidemic. Clin Chest Med. 2009;30(3):415-44, vii.

6 Pan WH, Lee MS, Chuang SY, Lin YC, Fu ML. Obesity pandemic, correlated factors and guidelines to define, screen and manage obesity in Taiwan. Obes Rev. 2008;9 Suppl 1:22-31.

7 Raoult D. Obesity pandemics and the modification of digestive bacterial flora. Eur J Clin Microbiol Infect Dis. 2008;27(8):631-4.

8 Kimenju SC, Rischke R, Klasen S, Qaim M. Do supermarkets contribute to the obesity pandemic in developing countries?. Public Health Nutr. 2015;:1-10.

9 Egger G, Swinburn B. An "ecological" approach to the obesity pandemic. BMJ. 1997;315(7106):477-80.

10 Barton M, Furrer J. Cardiovascular consequences of the obesity pandemic: need for action. Expert Opin Investig Drugs. 2003;12(11):1757-9.

11 James PT, Leach R, Kalamara E, Shayeghi M. The worldwide obesity epidemic. Obes Res. 2001;9 Suppl 4:228S-233S.

12 Mcallister EJ, Dhurandhar NV, Keith SW, et al. Ten putative contributors to the obesity epidemic. Crit Rev Food Sci Nutr. 2009;49(10):868-913.

13 Hurt RT, Kulisek C, Buchanan LA, Mcclave SA. The obesity epidemic: challenges, health initiatives, and implications for gastroenterologists. Gastroenterol Hepatol (N Y). 2010;6(12):780-92.

14 Urquhart CS, Mihalynuk TV. Disordered eating in women: implications for the obesity pandemic. Can J Diet Pract Res. 2011;72(1):e115-25.

15 Hebert JR, Allison DB, Archer E, Lavie CJ, Blair SN. Scientific decision making, policy decisions, and the obesity pandemic. Mayo Clin Proc. 2013;88(6):593-604.

16 Spanier PA, Marshall SJ, Faulkner GE. Tackling the obesity pandemic: a call for sedentary behaviour research. Can J Public Health. 2006;97(3):255-7.

17 Prentice AM. The emerging epidemic of obesity in developing countries. Int J Epidemiol. 2006;35(1):93-9.

18 Valiquette L, Sirard S, Laupland K. A microbiological explanation for the obesity pandemic?. Can J Infect Dis Med Microbiol. 2014;25(6):294-5.

19 Mozaffarian D. The great fat debate: taking the focus off of saturated fat. J Am Diet Assoc. 2011;111(5):665-6.

20 Hu FB, Stampfer MJ, Rimm E, et al. Dietary fat and coronary heart disease: a comparison of approaches for adjusting for total energy intake and modeling repeated dietary measurements. Am J Epidemiol. 1999;149(6):531-40.

21 Willett WC, Leibel RL. Dietary fat is not a major determinant of body fat. Am J Med. 2002;113 Suppl 9B:47S-59S.

22 Gardner CD, Kiazand A, Alhassan S, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial. JAMA. 2007;297(9):969-77.

23 Brownell KD, Kersh R, Ludwig DS, et al. Personal responsibility and obesity: a constructive approach to a controversial issue. Health Aff (Millwood). 2010;29(3):379-87.

24 Puhl RM, Brownell KD. Psychosocial origins of obesity stigma: toward changing a powerful and pervasive bias. Obes Rev. 2003;4(4):213-27.

25 Battle EK, Brownell KD. Confronting a rising tide of eating disorders and obesity: treatment vs. prevention and policy. Addict Behav. 1996;21(6):755-65.

26 Gardner CD, Kiazand A, Alhassan S, et al. Comparison of the Atkins, Zone, Ornish, and LEARN diets for change in weight and related risk factors among overweight premenopausal women: the A TO Z Weight Loss Study: a randomized trial. JAMA. 2007;297(9):969-77.

27 Cohen DA, Sturm R, Scott M, Farley TA, Bluthenthal R. Not enough fruit and vegetables or too many cookies, candies, salty snacks, and soft drinks?. Public Health Rep. 2010;125(1):88-95.

28 Reedy J, Krebs-smith SM. Dietary sources of energy, solid fats, and added sugars among children and adolescents in the United States. J Am Diet Assoc. 2010;110(10):1477-84.

29 Ingram DK, Roth GS. Calorie restriction mimetics: can you have your cake and eat it, too?. Ageing Res Rev. 2015;20:46-62.

30 Feinman RD, Fine EJ. "A calorie is a calorie" violates the second law of thermodynamics. Nutr J. 2004;3:9.

31 Purnell JQ. Obesity: Calories or content: what is the best weight-loss diet?. Nat Rev Endocrinol. 2009;5(8):419-20.

32 Jakubowicz D, Barnea M, Wainstein J, Froy O. High caloric intake at breakfast vs. dinner differentially influences weight loss of overweight and obese women. Obesity (Silver Spring). 2013;21(12):2504-12.

33 Lichtman SW, Pisarska K, Berman ER, et al. Discrepancy between self-reported and actual caloric intake and exercise in obese subjects. N Engl J Med. 1992;327(27):1893-8.

34 Lieber CS. Perspectives: do alcohol calories count?. Am J Clin Nutr. 1991;54(6):976-82.

35 Brehm BJ, Seeley RJ, Daniels SR, D'alessio DA. A randomized trial comparing a very low carbohydrate diet and a calorie-restricted low fat diet on body weight and cardiovascular risk factors in healthy women. J Clin Endocrinol Metab. 2003;88(4):1617-23.

36 Wing RR, Phelan S. Long-term weight loss maintenance. Am J Clin Nutr. 2005;82(1 Suppl):222S-225S.

37 Pilot randomized trial demonstrating reversal of obesity-related abnormalities in reward system responsivity to food cues with a behavioral intervention. Nutrition & Diabetes. 2014;4(9):e129.

38 Jenkins DJ, Kendall CW, Marchie A, Augustin LS. Too much sugar, too much carbohydrate, or just too much?. Am J Clin Nutr. 2004;79(5):711-2.

39 Bleich SN, Wolfson JA, Jarlenski MP. Calorie changes in chain restaurant menu items: implications for obesity and evaluations of menu labeling. Am J Prev Med. 2015;48(1):70-5.

40 Yang Q, Zhang Z, Gregg EW, Flanders WD, Merritt R, Hu FB. Added sugar intake and cardiovascular diseases mortality among US adults. JAMA Intern Med. 2014;174(4):516-24.

41 Stanhope KL, Bremer AA, Medici V, et al. Consumption of fructose and high fructose corn syrup increase postprandial triglycerides, LDL-cholesterol, and apolipoprotein-B in young men and women. J Clin Endocrinol Metab. 2011;96(10):E1596-605.

42 Stefanidis A, Watt MJ. Does too much sugar make for lost memories?. J Physiol (Lond). 2012;590(Pt 16):3633-4.

43 Casagrande SS, Wang Y, Anderson C, Gary TL. Have Americans increased their fruit and vegetable intake? The trends between 1988 and 2002. Am J Prev Med. 2007;32(4):257-63.

44 Agrawal R, Gomez-pinilla F. 'Metabolic syndrome' in the brain: deficiency in omega-3 fatty acid exacerbates dysfunctions in insulin receptor signalling and cognition. J Physiol (Lond). 2012;590(Pt 10):2485-99.

45 Avena NM, Rada P, Hoebel BG. Evidence for sugar addiction: behavioral and neurochemical effects of intermittent, excessive sugar intake. Neurosci Biobehav Rev. 2008;32(1):20-39.

46 De koning L, Malik VS, Kellogg MD, Rimm EB, Willett WC, Hu FB. Sweetened beverage consumption, incident coronary heart disease, and biomarkers of risk in men. Circulation. 2012;125(14):1735-41, S1.

47 Ishimoto T, Lanaspa MA, Le MT, et al. Opposing effects of fructokinase C and A isoforms on fructose-induced metabolic syndrome in mice. Proc Natl Acad Sci USA. 2012;109(11):4320-5.

48 Bray, George et al. Consumption of high fructose corn syrup in beverages may play a role in the epidemic of obesity. American Journal of Clinical Nutrition Vol. 79, no. 4, p. 537-543, April 2004.

49 Soda and Sugary Beverages linked with Diabetes, Metabolic Syndrome, V. S. Malik, B. M. Popkin, G. A. Bray, J.-P. Despres, W. C. Willett, F. B. Hu. Sugar Sweetened Beverages and Risk of Metabolic Syndrome and Type 2 Diabetes: A Meta-analysis.Diabetes Care, 2010

50 Pollock NK, Bundy V, Kanto W, et al. Greater fructose consumption is associated with cardiometabolic risk markers and visceral adiposity in adolescents. J Nutr. 2012;142(2):251-7.

51 Booth FW, Roberts CK, Laye MJ. Lack of exercise is a major cause of chronic diseases. Compr Physiol. 2012;2(2):1143-211.

52 Caudwell P, Hopkins M, King NA, Stubbs RJ, Blundell JE. Exercise alone is not enough: weight loss also needs a healthy (Mediterranean) diet?. Public Health Nutr. 2009;12(9A):1663-6.

53 Hamilton MT, Healy GN, Dunstan DW, Zderic TW, Owen N. Too Little Exercise and Too Much Sitting: Inactivity Physiology and the Need for New Recommendations on Sedentary Behavior. Curr Cardiovasc Risk Rep. 2008;2(4):292-298.

54 Akerstedt T, Knutsson A, Westerholm P, Theorell T, Alfredsson L, Kecklund G. Sleep disturbances, work stress and work hours: a cross-sectional study. J Psychosom Res. 2002;53(3):741-8.

55 Han KS, Kim L, Shim I. Stress and sleep disorder. Exp Neurobiol. 2012;21(4):141-50.

56 Kant GJ, Pastel RH, Bauman RA, et al. Effects of chronic stress on sleep in rats. Physiol Behav. 1995;57(2):359-65.

57 Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol. 2005;25(1):117-29.

58 Pilcher JJ, Huffcutt AI. Effects of sleep deprivation on performance: a meta-analysis. Sleep. 1996;19(4):318-26.

59 Kripke DF, Garfinkel L, Wingard DL, Klauber MR, Marler MR. Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry. 2002;59(2):131-6.

60 Tappy L, Lê KA. Metabolic effects of fructose and the worldwide increase in obesity. Physiol Rev. 2010;90(1):23-46.

61 Lê KA, Tappy L. Metabolic effects of fructose. Curr Opin Clin Nutr Metab Care. 2006;9(4):469-75.

62 Stanhope KL, Havel PJ. Fructose consumption: recent results and their potential implications. Ann N Y Acad Sci. 2010;1190:15-24.

63 Gaby AR. Adverse effects of dietary fructose. Altern Med Rev. 2005;10(4):294-306.

64 Lustig RH. Fructose: it's "alcohol without the buzz". Adv Nutr. 2013;4(2):226-35.

65 Leonardo CC, Doré S. Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins. Nutr Neurosci. 2011;14(5):226-36.

66 Su ZY, Shu L, Khor TO, Lee JH, Fuentes F, Kong AN. A perspective on dietary phytochemicals and cancer chemoprevention: oxidative stress, nrf2, and epigenomics. Top Curr Chem. 2013;329:133-62.

67 Paredes-gonzalez X, Fuentes F, Jeffery S, et al. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos. 2015;

68 Prasad KN. Simultaneous Activation of Nrf2 and Elevation of Dietary and Endogenous Antioxidant Chemicals for Cancer Prevention in Humans. J Am Coll Nutr. 2015;:1-10.

69 Pall ML, Levine S. Nrf2, a master regulator of detoxification and also antioxidant, anti-inflammatory and other cytoprotective mechanisms, is raised by health promoting factors. Sheng Li Xue Bao. 2015;67(1):1-18.

70 Milder JB, Liang LP, Patel M. Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet. Neurobiol Dis. 2010;40(1):238-44.

71 Harman D. Free radical theory of aging. Mutat Res. 1992;275(3-6):257-66.

72 Livesey G, Taylor R. Fructose consumption and consequences for glycation, plasma triacylglycerol, and body weight: meta-analyses and meta-regression models of intervention studies. Am J Clin Nutr. 2008;88(5):1419-37.

73 Lustig RH. Fructose: metabolic, hedonic, and societal parallels with ethanol. J Am Diet Assoc. 2010;110(9):1307-21.

74 Hofmann SM, Havel PJ. The good, the bad, and the unknown: Fructose and FGF21. Mol Metab. 2015;4(1):1-2.

75 Johnson RJ, Segal MS, Sautin Y, et al. Potential role of sugar (fructose) in the epidemic of hypertension, obesity and the metabolic syndrome, diabetes, kidney disease, and cardiovascular disease. Am J Clin Nutr. 2007;86(4):899-906.

76 Available at: //well.blogs.nytimes.com/2015/08/09/coca-cola-funds-scientists-who-shift-blame-for-obesity-away-from-bad-diets/. Accessed August 16, 2015.

77 Fowler SP, Williams K, Hazuda HP. Diet soda intake is associated with long-term increases in waist circumference in a biethnic cohort of older adults: the San Antonio Longitudinal Study of Aging. J Am Geriatr Soc. 2015;63(4):708-15.

78 Malik VS, Schulze MB, Hu FB. Intake of sugar-sweetened beverages and weight gain: a systematic review. Am J Clin Nutr. 2006;84(2):274-88.

79 Bocarsly ME, Powell ES, Avena NM, Hoebel BG. High-fructose corn syrup causes characteristics of obesity in rats: increased body weight, body fat and triglyceride levels. Pharmacol Biochem Behav. 2010;97(1):101-6.

80 Basaranoglu M, Basaranoglu G, Sabuncu T, Sentürk H. Fructose as a key player in the development of fatty liver disease. World J Gastroenterol. 2013;19(8):1166-72.

81 Feinman RD, Fine EJ. Fructose in perspective. Nutr Metab (Lond). 2013;10(1):45.

82 Cordain L, Eaton SB, Sebastian A, et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr. 2005;81(2):341-54.

83 O'keefe JH, Cordain L. Cardiovascular disease resulting from a diet and lifestyle at odds with our Paleolithic genome: how to become a 21st-century hunter-gatherer. Mayo Clin Proc. 2004;79(1):101-8.

84 Douard V, Ferraris RP. The role of fructose transporters in diseases linked to excessive fructose intake. J Physiol (Lond). 2013;591(Pt 2):401-14.

85 Port AM, Ruth MR, Istfan NW. Fructose consumption and cancer: is there a connection?. Curr Opin Endocrinol Diabetes Obes. 2012;19(5):367-74.

86 Konner M, Eaton SB. Paleolithic nutrition. Nutr Clin Pract. 2010;25:594–602.

87 Gross LS, Li L, Ford ES, Liu S. Increased consumption of refined carbohydrates and the epidemic of type 2 diabetes in the United States: an ecologic assessment. Am J Clin Nutr. 2004;79(5):774-9.

88 Available at: //www.ers.usda.gov/data-products/sugar-and-sweeteners-yearbook-tables.aspx. Accessed August 26, 2015.

89 Douard V, Ferraris RP. Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab. 2008;295(2):E227-37.

90 Kayano T, Burant CF, Fukumoto H, et al. Human facilitative glucose transporters. Isolation, functional characterization, and gene localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual glucose transporter pseudogene-like sequence (GLUT6). J Biol Chem. 1990;265(22):13276-82.

91 Luo S, Monterosso JR, Sarpelleh K, Page KA. Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards. Proc Natl Acad Sci USA. 2015;112(20):6509-14.

92 Funari VA, Crandall JE, Tolan DR. Fructose metabolism in the cerebellum. Cerebellum. 2007;6(2):130-40.

93 Molteni R, Barnard RJ, Ying Z, Roberts CK, Gómez-pinilla F. A high-fat, refined sugar diet reduces hippocampal brain-derived neurotrophic factor, neuronal plasticity, and learning. Neuroscience. 2002;112(4):803-14.

94 Crane PK, Walker R, Hubbard RA, et al. Glucose levels and risk of dementia. N Engl J Med. 2013;369(6):540-8.

95 Douard V, Ferraris RP. Regulation of the fructose transporter GLUT5 in health and disease. Am J Physiol Endocrinol Metab. 2008;295(2):E227-37.

96 Ferraris RP. Dietary and developmental regulation of intestinal sugar transport. Biochem J. 2001;360(Pt 2):265-76.

97 Buddington RK, Diamond JM. Ontogenetic development of intestinal nutrient transporters. Annu Rev Physiol 51: 601–619, 1989.

98 Jiang L, Ferraris R. Developmental reprogramming of rat GLUT-5 requires de novo mRNA and protein synthesis. Am J Physiol Gastrointest Liver Physiol 280: G113–G120, 2001.

99 Shu R, David ES, Ferraris RP. Luminal fructose modulates fructose transport and GLUT-5 expression in small intestine of weaning rats. Am J Physiol Gastrointest Liver Physiol 274: G232–G239, 1998.

100 Gugusheff JR, Ong ZY, Muhlhausler BS. A maternal "junk-food" diet reduces sensitivity to the opioid antagonist naloxone in offspring postweaning. FASEB J. 2013;27(3):1275-84.

101 Eny KM, Wolever TM, Fontaine-bisson B, El-sohemy A. Genetic variant in the glucose transporter type 2 is associated with higher intakes of sugars in two distinct populations. Physiol Genomics. 2008;33(3):355-60.

102 Alcock J, Maley CC, Aktipis CA. Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms. Bioessays. 2014;36(10):940-9.

103 Luo S, Monterosso JR, Sarpelleh K, Page KA. Differential effects of fructose versus glucose on brain and appetitive responses to food cues and decisions for food rewards. Proc Natl Acad Sci USA. 2015;112(20):6509-14.

104 Mate A, Barfull A, Hermosa AM, Planas JM, Vázquez CM. Regulation of D-fructose transporter GLUT5 in the ileum of spontaneously hypertensive rats. J Membr Biol. 2004;199(3):173-9.

105 Castelló A, Gumá A, Sevilla L, et al. Regulation of GLUT5 gene expression in rat intestinal mucosa: regional distribution, circadian rhythm, perinatal development and effect of diabetes. Biochem J. 1995;309 ( Pt 1):271-7.

106 Available at: //www.diabetes.org/advocacy/news-events/cost-of-diabetes.html. Accessed August 26, 2015.

107 Stuart CA, Howell ME, Yin D. Overexpression of GLUT5 in diabetic muscle is reversed by pioglitazone. Diabetes Care. 2007;30(4):925-31.

108 Schalkwijk CG, Stehouwer CD, Van hinsbergh VW. Fructose-mediated non-enzymatic glycation: sweet coupling or bad modification. Diabetes Metab Res Rev. 2004;20(5):369-82.

109 Murphy MP, Levine H. Alzheimer's disease and the amyloid-beta peptide. J Alzheimers Dis. 2010;19(1):311-23.

110 Sykiotis GP, Habeos IG, Samuelson AV, Bohmann D. The role of the antioxidant and longevity-promoting Nrf2 pathway in metabolic regulation. Curr Opin Clin Nutr Metab Care. 2011;14(1):41-8.

111 Holmström KM, Baird L, Zhang Y, et al. Nrf2 impacts cellular bioenergetics by controlling substrate availability for mitochondrial respiration. Biol Open. 2013;2(8):761-70.

112 Dinkova-kostova AT, Abramov AY. The emerging role of Nrf2 in mitochondrial function. Free Radic Biol Med. 2015;

113 Leonardo CC, Doré S. Dietary flavonoids are neuroprotective through Nrf2-coordinated induction of endogenous cytoprotective proteins. Nutr Neurosci. 2011;14(5):226-36.

114 Paredes-gonzalez X, Fuentes F, Jeffery S, et al. Induction of NRF2-mediated gene expression by dietary phytochemical flavones apigenin and luteolin. Biopharm Drug Dispos. 2015;

115 Jaramillo MC, Zhang DD. The emerging role of the Nrf2-Keap1 signaling pathway in cancer. Genes Dev. 2013;27(20):2179-91.