PhD Proposal

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Research Proposal

Currently in the UK 64% of adults are considered overweight or obese and contribute to the 1 in 3 adults worldwide who live with extra weight.  This number has quadrupled since 1980 and is growing most rapidly in the developing world where new economies are driving people away from traditional food to processed food with a lower nutrient content [1].  Besides the UK waistlines, there is also a growing population of patients exhibiting symptoms of Metabolic Syndrome which has been directly linked to increased risk of diabetes, high blood pressure, heart disease and stroke [2].  These diseases along with obesity treatment can cost the NHS over £33billion a year to treat and costs the economy far more in lost productivity.  It is projected that by 2050 the total cost of obesity will rise above £50billion [3].

Despite the UK public’s growing waistlines, their fascination with diets never falters.  Historically diets have focused on strict calorie restriction (Weight Watchers, Slimming World, MasterCleanse), macronutrient restriction (Atkins, South Beach, Zone) or meal replacement calorie restriction (SlimFast, Special K).  However many of these diets create a chronic cycle of weight loss followed by weight gain.  This is primarily due to the unsustainability of these diets when factored with the patient’s lifestyle or the ability to indefinitely restrict calories.  These factors result in 2 out of 3 dieters gaining both the weight that was lost plus additional weight over a five year period [4].  Newer on the diet scene are movements that seek to go back to less processed traditional foods and emphasise optimum nutrients through the selection of higher quality meats and traditional preparation (Primal, Paleo, SlowFood).

Dietary recommendations on micronutrient intake were established to prevent wasting diseases such as scurvy but very little is known about the optimal levels of many of the vitamins and minerals we eat everyday day and more importantly their impact on obesity [5] [6] [7] [8].  Deficiency of vitamins B-12, folic acid, B-6, C, E or minerals such as zinc or iron mimic DNA damage by radiation.  Increasing doses of B vitamins has also been shown to increase the binding affinity to a mutant polymorphisms and can reverse mitochondrial oxidative decay [9].  Vitamin D has been specifically linked with metabolic syndrome and the onset of morbid obesity [10] [11].  Specific micronutrient levels have been linked to the satiety hormone leptin and the drive to intake additional nutrients including; vitamin C, pyridoxine, pantothenic acid, folate, potassium,  magnesium, copper, chromium as well as some specific amino acids [12].  Additionally, a pilot study out of California examined cardiac disease and inflammation blood markers in a two weeks study which involved daily consumption of a fibre and nutrient rich bar demonstrating decreased levels in these specific markers [13].  Very little research has been conducted on how the body reacts to a nutrient rich diet from either natural sources or supplements, and if that can play a factor in caloric self-regulation and satiety through leptin even in a caloric deficit from exercise [14] [15].

The proposed project will look at the underlying mechanisms and genetics behind the obesity epidemic with the goal to define intervention and treatment for sustainable weight loss.  Firstly a meta-analysis will be to create a comprehensive library of potential targets including known SNPs already studied such as MTHFR, PPARD, TCF7L2 and KRS2 [16] [17].  Targets will come from three categories; micronutrient metabolism and sensing, satiety and hunger hormones including ghrelin and leptin, and insulin sensitivity and response [18] [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29].  These targets will create a library for screening patients during the clinical phase.  Secondly we will study in-vitro the bioavailability of nutrients from whole foods compared to traditional supplement formulation.  Traditional “functional food” preparations such as soaking and fermentation will also be examined to see how these processes quantitatively effects nutrient availability and the decreases of the presence of anti-nutrients such as phytic and oxalic acid [30].  The clinical experiment is comprised of a combination of acute and prolonged response to increased nutrient availability through food, supplementation or both.  Patients will be tested for potential polymorphisms in identified SNPs and their response to specific nutrients will be additionally monitored.  Data will be collected over 6 months.  Full bloodwork for lipids, cholesterol, inflammation, micronutrients as well as glucose tolerance testing will be performed at the 0, 3 and 6 month marks using previous methods for serum testing [31].  Acute response to exercise and diet with specific measures of ghrelin, leptin and insulin will be measured at the same intervals [32] [33] [34].  We hope to find that SNPs in specific nutrient or hormone pathways will correlate to insufficient levels of leptin and ghrelin causing caloric dysregulation.  In addition the response to exercise when on a high nutrient diet will not result and an acute increased demand for calories as leptin levels will be stabilized over time and ghrelin will decrease in a larger amount then previously recorded due to fat loss [35] [36].

References

[1] S. Keats and S. Wiggans, “Future diets: implications for agriculture and food price,” Overseas Development Institute, London, 2014.
[2] NHS, “Metabolic Syndrome,” 10 12 2014. [Online]. Available: http://www.nhs.uk/conditions/metabolic-syndrome/Pages/Introduction.aspx. [Accessed 3 3 2015].
[3] Diabetes.co.uk, “Cost of Diabetes,” [Online]. Available: http://www.diabetes.co.uk/cost-of-diabetes.html. [Accessed 3 3 2015].
[4] BBC, “Many dieters ‘finish up heavier’,” 10 April 2007.
[5] O. P. García, K. Long and J. Rosado, “Impact of micronutrient deficiencies on obesity,” Nutrition Reviews, vol. 67, no. 10, pp. 559-572, 2009.
[6] B. N.Ames, “Increasing longevity by tuning up metabolism,” EMBO Reports, vol. 6, pp. S20-S24, 2005.
[7] G. Zavala and e. al, “Specific micronutrient concentrations are associated with inflammatory cytokines in a rural population of Mexican women with a high prevalence of obesity,” British Journal of Nutrition, vol. 109, pp. 686-694, 2013.
[8] B. N. Ames, “The Metabolic Tune-Up: Metabolic Harmony and Disease Prevention,” The Journal of Nutrition, pp. 1544S-1548S, 2003.
[9] B. N. Ames, “A role for supplements in optimizing health: the metabolic tune-up,” Archives of Biochemistry and Biophysics, vol. 423, pp. 227-234, 2003.
[10] J. I. Botella-Carretero and e. al, “Vitamin D deficiency is associated with the metabolic syndrome in morbid obesity,” Clinical Nutrition, vol. 26, pp. 573-580, 2007.
[11] Y. Foss, “Vitamin D deficiency is the cause of common obesity,” Medical Hypothesis, vol. 72, pp. 314-321, 2009.
[12] J. Licinio and e. al, “Effects of leptin on intake of specific micro- and macronutrientsin a woman with leptin gene deficiency studied off and on leptinat stable body weight,” Appetite, vol. 49, pp. 594-599, 2007.
[13] M. L. Mietus-Snyder and e. al, “A nutrient-dense, high-fiber, fruit-based supplement bar increases HDL cholesterol, particularly large HDL, lowers homocysteine, and raises glutathione in a 2-wk trial,” The FASEB Journal, vol. 26, pp. 3515-3527, 2012.
[14] A. A. ROBSON, “PREVENTING DIET INDUCED DISEASE: BIOAVAILABLE NUTRIENT-RICH, LOWENERGY-DENSE DIETS,” Nutrition and Health, vol. 20, pp. 135-166, 2009.
[15] M. W. Hulver and J. Houmard, “Plasma Leptin and Exercise,” Sports Medicine, vol. 33, no. 7, pp. 473-482, 2003.
[16] A. Haupt and e. al, “Gene Variants of TCF7L2 Influence Weight Loss and Body Composition During Lifestyle Intervention in a Population at Risk for Type 2 Diabetes,” Diabetes, vol. 59, pp. 747-750, 2010.
[17] C. Thamer and e. al, “Variations in PPARD Determine the Change in Body Composition during Lifestyle Intervention: A Whole-Body Magnetic Resonance Study,” Journal of Clinical Endocrinological Metabolism, vol. 93, no. 4, pp. 1497-1500, 2008.
[18] A. Baessler and e. al, “Genetic Linkage and Association of the Growth Hormone Secretagogue Receptor (Ghrelin Receptor) Gene in Human Obesity,” Diabetes, vol. 54, pp. 259-267, 2005.
[19] E. R. Grimm and N. Steinle, “Genetics of eating behavior: established and emerging concepts,” Nutrition Reviews, vol. 69, pp. 50-62, 2011.
[20] S. Bloom, K. Wynne and O. Chaudhri, “Gut feeling – the secret of satiety?,” Clinical Medicine, vol. 5, pp. 147-152, 2005.
[21] G. S. Hotamisligil1, “Inflammation and metabolic disorders,” Nature, vol. 444, pp. 860-867, 2006.
[22] J. P. McClung and P. Carl, “Iron deficiency and obesity: the contribution of inflammation and diminished iron absorption,” Nutrition Reviews, vol. 67, no. 2, pp. 100-104, 2008.
[23] M. MILAGROS G. HUERTA and e. al, “Magnesium Deficiency Is Associated With Insulin Resistance in Obese Children,” Diabetes Care, vol. 28, no. 5, pp. 1175-1181, 2005.
[24] G. S. Hotamisligil and E. Erbay, “Nutrient sensing and inflammation in metabolic disease,” Nature Reviews, vol. 8, pp. 923-934, 2008.
[25] B. v. Ommen and R. Stieum, “Nutrigenomics: exploiting systems biology in the nutrition and health arena,” Current Opinions in Biotechnology, vol. 13, pp. 517-521, 2002.
[26] M. F. McCarty, “Poor vitamin D status may contribute to high risk for insulin resistance, obesity, and cardiovascular disease in Asian Indians,” Medical Hypotheses, vol. 72, pp. 647-651, 2009.
[27] J. Korner and L. Aronne, “The emerging science of body weight regulation and its impact on obesity treatment,” The Journal of Clinical Investigation, vol. 111, no. 5, pp. 565-570, 2003.
[28] M. D. Klok and e. al, “The role of leptin and ghrelin in the regulation of food intake and body weight in humans: a review,” Obesite Reviews, vol. 8, pp. 21-34, 2007.
[29] U. Mager and e. al, “Variations in the Ghrelin Receptor Gene Associate with Obesity and Glucose Metabolism in Individuals with Impaired Glucose Tolerance,” PLOS One, vol. 3, no. 8, p. e2941, 2008.
[30] P. M. Verschuren, “Functional Foods: Scientific and Global Perspectives,” British Journal of Nutrition, vol. 88, pp. S125-S130, 2002.
[31] R. S. Rector and e. al, “Exercise and diet induced weight loss improves measures of oxidative stressand insulin sensitivity in adults with characteristics of the metabolic syndrome,” American Journal of Physiology- Endrocrinology and Metabolism, vol. 293, pp. 500-506, 2007.
[32] U. Mager and e. al, “Expression of ghrelin gene in peripheral blood mononuclearcells and plasma ghrelin concentrations in patients with metabolic syndrome,” European Journal of Endocrinology, vol. 158, pp. 499-510, 2008.
[33] E. Korek and e. al, “Fasting and postprandial levels of ghrelin, leptinand insulin in lean, obese and anorexic subjects,” Przegląd Gastroenterologiczny, vol. 8, no. 6, pp. 383-389, 2013.
[34] A. C. Soni and e. al, “Ghrelin, Leptin, Adiponectin, and Insulin Levels and Concurrent and Future Weight Change in Overweight Postmenopausal Women,” Menopause, vol. 18, no. 3, pp. 296-301, 2011.
[35] T. Ishii and e. al, “Effect of Exercise Training on Serum Leptin Levels in Type 2 Diabetic Patients,” Metabolism, vol. 60, no. 10, pp. 1136-1140, 2001.
[36] J. A. Houmard and e. al, “Effect of Short-Term Exercise Training on Leptin and Insulin Action,” Metabolism, vol. 49, no. 7, pp. 858-861, 2000.

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