Source: LOUISIANA STATE UNIVERSITY submitted to NRP
DIETARY FAT AND CENTRAL ADIPOSITY (THE METABOLIC SYNDROME)
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
COMPLETE
Funding Source
SPECIAL GRANT
Reporting Frequency
Annual
Accession No.
0195316
Grant No.
2003-34323-14010
Cumulative Award Amt.
(N/A)
Proposal No.
2004-06097
Multistate No.
(N/A)
Project Start Date
Sep 1, 2003
Project End Date
Aug 31, 2006
Grant Year
2004
Program Code
[GB]- (N/A)
Recipient Organization
LOUISIANA STATE UNIVERSITY
202 HIMES HALL
BATON ROUGE,LA 70803-0100
Performing Department
ADMINISTRATION
Non Technical Summary
Research activities during the past 3 years have identified several predictors for the storage of body fat, including a low maximal VO2, a high fasting insulin, and a high fasting respiratory quotient. Individuals with these variables are at higher risk of becoming obese, and exercise may be effective in overcoming this problem. This research addresses the very important topic of increased dietary fat or fat equivalents as one contributor to obesity, specifically the identification of the processes of adaptation to fat and fat equivalents.
Animal Health Component
40%
Research Effort Categories
Basic
50%
Applied
40%
Developmental
10%
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
7015010101050%
7025010102040%
7035010302010%
Knowledge Area
703 - Nutrition Education and Behavior; 702 - Requirements and Function of Nutrients and Other Food Components; 701 - Nutrient Composition of Food;

Subject Of Investigation
5010 - Food;

Field Of Science
3020 - Education; 1010 - Nutrition and metabolism; 1020 - Physiology;
Goals / Objectives
There is currently an epidemic of obesity in the United States. In a recent popular book, the introduction of palm oil and high fructose corn sweeteners into the American market, under USDA guidance, has provided the tools by which food marketers can "supersize" the American diet with obesity as its consequence. This project is designed to test the hypothesis that dietary fat contributes to the current epidemic of obesity. Four sets of studies are designed to examine the effects changing dietary fat on the metabolic and endocrine responses of healthy and overweight Americans. The first study will test the concept that higher initial levels of plasma insulin and lower maximal oxygen consumption during exercise will predict more fat storage during conditions of exposure to a high fat diet. For this first study, subjects will live in the room calorimeters while the percentage of fat in their diets is changed from 20% to 50% and back with measurement of hormonal and biochemical changes and metabolism of isolated muscle and fat cells. The second study will test the hypothesis that altered release of gut hormones such as ghrelin and glucagon-like peptide-1 might underlie the weight loss when dietary fat is partially replaced with indigestible olestra. The third study will be a pilot study to examine the hypothesis that fast foods produce different metabolic responses than comparable nutrients made from organic foods and different sources of protein. This study will be conducted by giving individuals 3 different meals over an interval of time and examining their acute response over the following few hours. The fourth study will be a pilot to measure the endocrine and metabolic response when subjects are fed high fructose corn sweeteners or artificial sweeteners as beverages or when combined with the solid food in the diet. Differences in the response of individuals will be evaluated using techniques of gene expression using biopsies of fat taken when they eat both high and low fat diets. This methodology will be part of all of the proposed studies to test the hypothesis that genetic and molecular differences underlie individual responses to diets.
Project Methods
Several questions remain to be answered regarding the fat storage syndrome and the adaptation to dietary fat. First, how robust are the predictors that we have identified? Are there other distinguishing biochemical, endocrine, and environmental characteristics of individuals who store fat when exposed to a high fat diet? This is important because if these individuals can be easily identified then dieatry interventions can be targeted to this "at-risk" population. Second, what is different about the individual with the "fat storage syndrome"? Are there cellular pathways that are dysregulated in the skeletal muscle of these individuals when compared to controls? Is the defect intrinsic, i.e. a diminished ability to conserve glucose and oxidize fat in skeletal muscle or alternately, is the phenotype due to environmental and dietary factors such as inactivity and energy excess? third, since we know that increased physical activity can reverse the "fat storage syndrome", what level of habitual physical activity is required for the individual with the "fat storage syndrome"? Fourth, the ability to "trick" the regulatory system for body fat by the replacment of dietary fat with olestra raises the question of the mechanisms for this. In this grant we will examine the hypothesis that the olestra in the intestine generates inhibitory signals from the GI track. Finally, we will do pilot tests on two other studies: (1) that the composition of a lunch can affect the "hormonal" response and (2) that putting high fructose corn sweeteners in solid food leads to different responses from the same sweetner in beverages. The following specific Aims will adress these questions: (1) We will characterize the biochemcial, endocrine, anthropometric, and environmental features of individuals with the fat storage syndrome. (2) We will identify the signaling pathways in skeletal muscle that are dysregulated in individuals with the fat storage syndrome through mRNA expression profiling and proteomics. (3) We will determine the role of environmental factors such as inactivity and caloric intake vs. intrinsic (genetic) factors in the fat storage syndrome. (4) We will identify the level of physical activity required to reverse the fat storage syndrome. (5) We will conduct a pilot study on the effect of changing the macronutrient sources of foods on hormonal and metabolic responses during lunch. (6) We will measure the changes in G.I. hormones (GLP-1, GIP, PYY3-36, and Ghrelin) to a standard meal or a meal in which 25% of the dietary fat has been replaced by olestra. Studies will be conducted at baseline weight and then after weight loss in overweight individuals. (7) We will conduct a pilot study on the effect of replacing sucrose with high fructose corn sweetners in beverages and solid foods by measuring the metabolic and hormonal responses.

Progress 09/01/03 to 08/31/06

Outputs
US Government agencies have called the rising prevalence of obesity an epidemic. Dietary fat has long been thought to play a role in this epidemic. Understanding the relation of dietary fat from animal and plant sources and how the body responds to them is the focus of our studies. We are testing the response of human subjects to changes in the quantity and quality of dietary fat on fat storage and the relationship of this fat storage to different amounts of dietary protein and exercise in a grant titled Dietary Fat and Central Adiposity. Central adiposity refers to the fat stored on or within the abdomen. The intraabdominal part of this fat is particularly important because it predicts risks for ill health. Our work has already yielded important new ideas. We have identified several predictors for the storage of body fat including a low maximal VO2, a high fasting insulin, and a high fasting respiratory quotient. Of particular interest is the fact that increased visceral fat stores predict further fat stores, as though it were a vicious cycle. We are currently trying to mimic the excess calories that people normally eat by varying both the protein and fat in young individuals living in the USDA funded metabolic unit. No data are yet available from this study. We are also examining the effects of higher and lower fat diets on the metabolic response to exercise, but here again, we are in the data collection phase. We have shown that a very important variable in the effects of a high fat diet is the size of the individual fat cell. As fat cells increase in size, the number of metabolic abnormalities also increases. The total number of fat cells does not have the same effect on metabolism. As few as three days of eating a high fat diet decreased the genetic expression in skeletal muscle of a cluster of genes involved in glucose uptake and oxidation and increased transcription of a key inhibitor of glucose conversion through the tricarboxylic acid cycle (PDHK4). These genes cluster with a second group of genes involved in mitochondrial fatty acid oxidation, the OXPHOS genes. These same genes are down-regulated in healthy young volunteers who are eating a high fat diet suggesting a mechanism by which high fat diets might be involved in the genesis of obesity and central adiposity. We have also shown that the maximal rate of fat oxidation during sleep when eating a high fat diet and mitochondrial DNA content are reduced in subjects with a family history of diabetes, supporting the concept of an intrinsic defect in oxidative capacity of muscle. We anticipate that these genes will be important in the responses to overfeeding and to exercise in the studies that are currently underway.

Impacts
These studies on response to dietary fat have identified several important groups of genes that relate to whether people store fat and have shown that individuals from families with a history of diabetes respond differently, providing the potential for targeting high risk people. We anticipate that exercise may allow people with these defects to reduce the negative consequences of eating a high fat diet.

Publications

  • Bray, G.A. and Hansen, B.C. 2006. The 20th anniverary of the International Association for the Study of Obesity: A review of two decades. Obesity Newsletter 9:13-15.
  • Chumlea, W.C., LaMonte, M.J. and Bray, G.A. 2006. Anthropometric assessment: Stature, weight and the body mass index (Adults). CRC Press (In press).
  • Lefevre, M., Lovejoy, J.C., Smith, S.R., Delany, J.P., Champagne, C., Most, M.M., Denkins, Y., de Jonge, L., Rood, J. and Bray, G.A. 2005. Comparison of the acute response to meals enriched with cis- or trans-fatty acids on glucose and lipids in overweight individuals with differing FABP2 genotypes. Metabolism 54:1652-1658.
  • Higami, Y., Barger, J.L., Page, G.P., Allison, D.B., Smith, S.R., Prolla, T.A. and Weindruch, R. 2006. Energy restriction lowers the expression of genes linked to inflammation, the cytoskeleton, the extracellular matrix, and angiogenesis in mouse adipose tissue. J Nutr 136:343-352.
  • Solinas, G., Summermatter, S., Mainieri, D., Gubler, M., Montani, J. P., Seydoux, J., Smith, S.R. and Dulloo, A.G. 2006. Corticotropin-releasing hormone directly stimulates thermogenesis in skeletal muscle possibly through substrate cycling between de novo lipogenesis and lipid oxidation. Endocrinology 147:31-38.
  • Larson-Meyer, D.E., Smith, S.R., Heilbronn, L.K., Kelley, D.E., Ravussin, E. and Newcomer, B.R. 2006. Muscle-associated triglyceride measured by Computed Tomography and Magnetic Resonance Spectroscopy. Obes. Res. 14:73-87.
  • Smith, S.R. and Wilson, P.W.F. 2006. Free fatty acids and atherosclerosis: Guilty or Innocent? Journal of Clinical Endocrinology and Metabolism 91:2506-2508.
  • Cefalu, W.T., Smith, S.R., Blonde, L. and Fonseca, V. 2006. The Hurricane Katrina aftermath and its impact on diabetes care: observations from "ground zero": lessons in disaster preparedness of people with diabetes. Diabetes Care 29:158-160.
  • Sparks, L.M., Xie, H., Koza, R.A., Mynatt, R., Bray, G.A. and Smith, S. R. 2006. High-fat/low-carbohydrate diets regulate glucose metabolism via a long-term transcriptional loop. Metabolism 55:1457-1463.
  • Sozen, M.A., de Jonge, L., Greenway, F., Ravussin, E., Smith, S.R. and Argyropoulos, G. 2006. A rare mutation in AgRP, +79G>A, affects promoter activity. European Journal of Human Genetics (Accepted).
  • Ukropcova, B., Sereda, O., de Jonge, L., Bogacka, I., Nguyen, T., Xie, H., Bray, G.A. and Smith, S.R. 2006. Family history of diabetes links impaired substrate switching and reduced mitochondrial content in skeletal muscle. Diabetes (In review).
  • DeLany, J.P., Bray, G.A., Harsha, D.W. and Volaufova, J. 2006. Energy expenditure and substrate oxidation predict change in body fat in children. Am J Clin Nutr (In press).
  • Bray, G.A. 2006. Obesity: the disease. J Med Chem 49:4001-7.
  • Popkin, B.M., Armstrong, L.E., Bray, G.A., Caballero, B., Frei, B. and Willett, W.C. 2006. A new proposed guidance system for beverage consumption in the United States. Am J Clin Nutr 83:529-542.
  • McElroy, S.L, Allison, D.B. and Bray, G.A. (editors). 2006. Obesity and Mental Disorders. New York: Taylor and Francis Group, pp i-xviii, 1-462.
  • Bray, G.A. and Ryan, D.H. 2005. Medical approaches to treatment of the obese patient. IN: Obesity and Diabetes, C.S. Mantzoros (ed). Chap 26 Totowa, NJ: Humana Press, pp 457-468.
  • Kennedy, B.M., Paeratakul, S., Ryan, D.H. and Bray, G.A. 2006. Socioeconomic status and health disparity in the United States. J Human Behav Soc Environment (In press).
  • Bray, G.A. and Bellanger, T. 2006. Epidemiology, trends, and morbidities of obesity and the metabolic syndrome. Endocrine 29:109-117.
  • Poirier, P., Giles, T.D., Bray, G.A., Hong, Y., Stern, J.S., Pi-Sunyer, F.X., and Eckel, R.H. 2006. Obesity and cardiovascular disease: pathophysiology, evaluation and effect of weight loss. Arterio Thomb Vasc Biol 26:968-976.


Progress 01/01/05 to 12/31/05

Outputs
US Government agencies have called the rising prevalence of obesity an epidemic. Dietary fat has long been thought to play a role in this epidemic. Understanding the relation of dietary fat from animal and plant sources and how the body responds to them is the focus of our studies. We are testing the response of human subjects to changes in the quantity and quality of dietary fat on fat storage and the relationship of this fat storage to different amounts of dietary protein and exercise in a grant titled Dietary Fat and Central Adiposity. Central adiposity refers to the fat stored on or within the abdomen. The intraabdominal part of this fat is particularly important because it predicts risks for ill-health. Our work has already yielded important new ideas. We have identified several predictors for the storage of body fat including a low maximal VO2, a high fasting insulin, and a high fasting respiratory quotient. Of particular interest is the fact that increased visceral fat stores predict further fat stores, as though it were a vicious cycle. We have shown that these predictors are present in overweight men and women, as well as normal weight ones. Using muscle biopsies from the individuals eating different levels of dietary fat, we have identified two key pathways affected by a high fat diet. Three days of a high fat diet decreased mRNA in skeletal muscle for a cluster of genes involved in glucose uptake and oxidation and increased transcription of a key inhibitor of glucose conversion through the tricarboxylic acid cycle (PDHK4). These genes cluster with a second group of genes involved in mitochondrial fatty acid oxidation called the OXPHOS genes. These same genes are down regulated in healthy young volunteers who are eating a high fat diet suggesting a mechanism by which high fat diets might be involved in the genesis of obesity and central adiposity. We have also shown that the maximal rate of fat oxidation during sleep when eating a high fat diet and mitochondrial DNA content are reduced in subjects with a family history of diabetes, supporting the concept of an intrinsic defect in oxidative capacity of muscle fat. From our earlier study feeding olestra to healthy subjects, we have shown that olestra reduces the concentration of some of the fat soluble vitamins in plasma, and we are currently testing the effect of olestra on removal of organochlorine molecules from adipose tissue during weight loss.

Impacts
These studies on response to dietary fat have identified several important groups of genes that relate to whether people store fat and have shown that individuals from families with a history of diabetes respond differently, providing the potential for targeting high risk people.

Publications

  • Tulley, R.T., Vaidyanathan, J., Wilson, J., Rood, J., Lovejoy, J.C., Most, M.M., Volaufova, J., Peters, J.C. and Bray, G.A. 2005. Daily intake of multivitamins during long-term intake of olestra in men prevents declines in serum vitamins A and E but not carotenoids J Nutr 135:1465-1461.
  • Bogacka, I., Xie, H., Bray, G.A. and Smith, S.R. 2005. Pioglitazone induces mitochondrial biogenesis in human subcutaneous adipose tissue in vivo. Diabetes 54(5):1392-1399.
  • Newton, R.L. Jr, Alfonso, A., White, M.A., York-Crowe, E., Walden, H., Ryan, D., Bray, G.A. and Williamson, D. 2005. Percent body fat measured by BIA and DEXA in obese, African American adolescent girls. Intern J Obes 29:594-602.
  • Bray, G.A. 2005. Epidemiology, risks and pathogenesis of obesity. Meat Sci 71:2-7.
  • Ukropcova, B., McNeil, M., Levitan, L., Sereda, O., Xie, H., Bray, G.A. and Smith S.R. 2005. Dynamic changes in fat oxidation in human primary myocytes mirror metabolic characteristics of the donor. J Clin Invest 115:1934-1941.
  • Sparks, L., Xie, H., Koza, R., Bray, G. and Smith, S. 2005. A high fat diet coordinately down regulates genes required for mitochondrial oxidative phosphorylation in skeletal muscle. Diabetes 54:1926-1933.
  • Lefevre, M., Lovejoy, J.C., Smith, S.R., DeLany, J.P., Champagne, C., Most, M.M., Denkins, Y., de Jonge, L., Rood, J. and Bray, G.A. 2005. Comparison of the acute response to meals enriched with cis- or trans-fatty acid on glucose and lipids in overweight individuals with differing FABP-2 genotypes. Metabolism 54:1652-1658.
  • Bray, G.A. and Ryan, D.H. 2005. Medical approaches to treatment of the obese patient. IN: Obesity and Diabetes, C.S. Mantzoros (ed). Chap 26 Totowa, NJ: Humana Press, pp 457-468.
  • Poirier, P., Giles, T.D., Bray, G.A., Hong, Y., Stern, J.S., Pi-Sunyer, F.X. and Eckel, R.H. 2005. Obesity and cardiovascular disease: Pathophysiology, evaluation and effects of weight loss. An update of the 1997 American Heart Association scientific statement on obesity and heart disease from the Obesity Committee of the Council on Nutrition, Physical Activity and Metabolism.
  • Bellanger, T.M. and Bray, G.A. 2005. Obesity related morbidity and mortality. J La State Med Soc 157 (Spec No 1):S42-49.
  • Bray, G.A. 2005. Drug Treatment of Obesity. Psychiatric Clin N Am 28:193-217.
  • Bray, G.A. 2005. Is there something special about low carbohydrate diets? Ann Int Med 142:469-470 (ed).
  • Bray, G.A. 2005. Pharmacological Treatment of Obesity IN: Obesity and Binge Eating Disorder, S. Munsch and C. Beglinger (eds) Bibliotheca Psychiatrica No 171:81-101, Karger, Basel.
  • Bray, G.A. 2005. Drug insight: appetite suppressants. Nature Clin Prac Gastroenterol Hepatol 2:89-95.


Progress 01/01/04 to 12/31/04

Outputs
Specific Objectives: a) to characterize the baseline biochemical, endocrine and anthropometric predictors for fat storage in healthy men and women eating diets that are altered in the percentage of fat; b) to characterize the differences between healthy men and women and overweight men and women as they eat diets with different levels of dietary fat; c) to examine the signaling pathways in skeletal muscle from individuals fed different levels of dietary fat through mRNA expression profiling and proteomics; d) to compare the effects of a fast-food versus a healthy alternative lunch on hormonal and metabolic responses in healthy individuals; e) to measure the changes in gastrointestinal hormones after eating a 33% fat diet, a 25% fat diet or a 33% fat diet in which 1/3 of the fat is replaced by olestra and f) to test the effects of three levels of protein on the metabolic responses to overfeeding in healthy men and women and overweight men and women. For aims a) and b) the database has been locked, and data are being used to support publications of papers related to the subsequent aims. For aim c) we have identified two key pathways affected by a high fat diet after developing an 18, 861 gene RNA microarray. Three days of a high fat diet decreased mRNA in skeletal muscle for a cluster of genes involved in glucose uptake and oxidation and increased transcription of a key inhibitor of glucose conversion through the tricarboxylic acid cycle (PDHK4). These genes cluster with a second group of genes involved in mitochondrial fatty acid oxidation and are called the OXPHOS genes. These same genes are down-regulated in healthy young volunteers who are eating a high fat diet, suggesting a mechanism by which high fat diets might be involved in the genesis of obesity and the metabolic syndrome. Additional studies in cultured skeletal muscle cells from these same volunteers suggest that impaired capacity to oxidize dietary fat is an epigenetic or genetic trait. For objective d) the study is complete and interestingly, there was no difference in the metabolic and endocrine response whether the lunch meal came from a fast-food restaurant or from a nutritious alternative with the same protein and energy content. For objective e), the collection of data for the first 20 subjects eating each of 3 meals, one of which contained olestra, is complete, and the analyses of gastrointestinal hormones and metabolic parameters are underway. For the final objective, f, the diets have been designed, and recruitment of subjects is underway.

Impacts
Dietary fat and central adiposity (the metabolic syndrome) are major problems in the United States. The baseline biochemical, endocrine, and anthropometric predictors for fat storage in healthy men and women eating diets altered in the percentage of fat will be examined. These studies are designed to provide insights into the role of dietary fats in the current obesity epidemic and to examine how changing dietary fat affects the metabolic and endocrine responses of healthy and overweight Americans.

Publications

  • Bray, G.A. 2004. Obesity is a chronic, relapsing neurochemical disease. Intern J Obes 28:34-38.
  • Bray, G.A. and Champagne, C.M. 2004. Obesity and the metabolic syndrome. JADA 104:86-89.
  • Bray, G.A. 2004. Do not throw the baby out with the bath water. Am J Clin Nutr 79:347-349 (editorial).
  • Bray, G.A. (Ed). 2004. Office Management of Obesity. Philadelphia: Saunders, 1-311.
  • Bray, G.A. 2004. Preface. IN: Office Management of Obesity. G.A. Bray (ed). Philadelphia: Saunders, p xi.
  • Bray, G.A. 2004. The FLUORIDE hypothesis and DIOBESITY: How to prevent diabetes by preventing obesity. IN: Progress in Obesity Research 9. Medeiros-Neto, G., Halpern, A. and Bouchard, C. (eds). London: John Libbey, pp 26-28.
  • Bray, G.A. 2004. Treatment of Obesity. IN: Encyclopedia of Endocrine Diseases. Martini , L. (ed). Amsterdam:Elsevier, 4 vols.
  • Bray, G.A. 2004. Obesity, Treatment of. IN Encyclopedia of Gastroenterology. New York: Academic Press, pp 1-4.
  • Bray, G.A., Hu, F., Greene, P.J., Kumanyika, S., Willett, W.C. and Glickman, D. 2004. Food fight: Calories, carbohydrates and thermodynamics. AAAS 170th annual meeting, Seattle, WA;S33.
  • Bray, G.A., Nielsen, S.J. and Popkin, B.M. 2004. High fructose corn syrup and the epidemic of obesity. Am J Clin Nutr 79: 537-544.
  • Caterson, I.D., Hubbard, V., Bray, G.A., Grunting, R., Hansen, B.C., Hong, Y., Laborite, D., Slidell, J.C. and Smith, Jr., S.C. 2004. American Heart Association. Prevention Conference VII: Obesity, a world-wide epidemic related to heart disease and stroke: Group III World-wide co-morbidities of obesity. Circulation 110:e476-e483.
  • Bray, G.A. 2004. Medical Consequences of Obesity. J Clin Endocrinol Metab 89:2583-2589.
  • Guo, X, Warden, B.A., Paeratakul, S. and Bray, G.A. 2004. Healthy Eating Index and Obesity. Eur J Clin Nutr 19:(E-pub May 19) (PMID 15220243.
  • Bogacka, I.U., Bray, G.A. and Smith, S.R. 2004. Pioglitazone increases mitochondrial number and fatty acid oxidation in human adipose tissue. Endocrine Society: 237 (Abs).
  • Sparks, L.M., Bray, G.A., Xie, H., Koza, R.A. and Smith, S.R. 2004. Short-term high fat diet coordinately down regulates carbohydrate metabolism genes in healthy young men. Endocrine Society:319 (Abs).
  • Bogacka, L., Xie, H., Bray, G.A. and Smith, S.R. 2004. The effect of pioglitazone on peroxisome proliferator-activated receptor-target genes related to lipid storage in vivo. Diab Care 27:1660-1667.
  • Bray, G.A. 2004. Reply to J. Bigaard et al. Am J Clin Nutr 80:000-000 (letter to the editor).
  • Bray, G.A., Nielsen, S.J. and Popkin, B.M. 2004. Reply to Michael Jacobson. Am J Clin Nutr 80:000-000 (Letter to the editor).
  • Bray, G.A., Nielsen, S.J. and Popkin, B.M. 2004. Erratum: Figure 1. Am J Clin Nutr 80:000-000.
  • Bray, G.A., Nielsen, S.J. and Popkin, B.M. 2004. Reply to Nicholas Krilanovich. Am J Clin Nutr 80:000-000 (Letter to the Editor).
  • Bray, G.A. 2004. The epidemic of obesity and changes in food intake: The Fluoride Hypothesis. Physiol Behav 82:115-121.
  • Bray, G.A. 2004. How do we get fat? An epidemiological and metabolic approach. Clin Dermatol 22:281-288.
  • Bugrake, I., Bray, G.A. and Smith, S.R. 2004. The effect of pioglitazone on mitochondrial number and fatty acid oxidation in human adipose tissue. ECO Intern J (Abs).
  • Smith S.R., Xie, H., Bogacka, I., Baghian, S., McNeil, M., Morris, A., Eckel, R. and Bray, G.A. 2004. Subtyping diobesity: an adipose tissue perspective. Obes Res 12:A30 (Abs).
  • Stewart, T.M., Williamson, D.A., Rzeznikiewicz, A., Bray, G.A. and the Look AHEAD Research Group. 2004. Body Shape and Weight Goals in Obesity and type 2 Diabetes: All Goals are not Created Equal. Obes Res 12:A83 (Abs).
  • Klein, S., Burke, L.E., Bray, G.A., Blair, S., Allison, D.B., Pi-Sunyer, S., Hong, Y. and Eckel, R.H. 2004. American Heart Association Council on Nutrition, Physical Activity, and Metabolism: American College of Cardiology Foundation. Clinical implications of obesity with specific focus on cardiovascular disease. Circ 110:2952-2967.
  • Bray, G.A., Paeratakul, S. and Popkin, B.M. 2004. Dietary fat and obesity: A review of animal, clinical and epidemiological studies. Physiol & Behav 83: 549-555.
  • Bellanger, T.M. and Bray, G.A. 2004. Obesity-related morbidity and mortality. Louisiana Medicine, 156.
  • Smith, S.R. and Ravussin, E. 2005. Genetic and physiological factors in obesity. The Journal of the Louisiana State Medical Society Supplement on Obesity 156:S12-S18.
  • Smith, S.R. 2004. Metabolic syndrome targets. Curr Drug Targets CNS Neurol Disord 3:431-439.
  • Bray, G.A., Smith, S.R., Most, M., Rood, J. and Redmann, S. 2004. Hormonal responses to a fast food meal compared with nutritionally comparable meals of different composition. Obes Res 12:A100 (Abs).
  • Sparks, L., Xie, H., Koza, R., Bray, G. and Smith, S. 2004. Short-term high fat diet coordinately down regulated oxidative phosphorylation genes in healthy young men. Obes Res 12:A178 (Abs).
  • Ukropcova, B., McNeil, M. Bray, G. and Smith, S.R. 2004. Metabolic inflexibility is an intrinsic quality of muscle cells. Obes Res 12:A180 (Abs).
  • Champagne, C., Ryan, D., Paeratakul, S., LeBlanc, E. and Bray, G. 2004. Politics of the Obesity Epidemic. Results of the Louisiana Physicians Survey. Obes Res 12:A191 (Abs).


Progress 01/01/03 to 12/31/03

Outputs
Specific objectives: a) characterize the baseline biochemical, endocrine, and anthropometric predictors for fat storage in healthy men and women eating diets that are altered in the percentage of fat; b)characterize the differences between healthy men and women and overweight men and women as they eat diets with different levels of dietary fat; c) examine the signaling pathways in skeletal muscle from individuals with the fat storage syndrome through mRNA expression profiling and proteomics; d) determine the role of physical activity and caloric intake versus genetic factors in the adaptation to a high fat diet; e) compare the effects of a fast-food versus a healthy-alternatives lunch on hormonal and metabolic responses in healthy individuals; f) measure the changes in gastrointestinal hormones after eating a 33% fat diet, a 25% fat diet or a 33% fat diet in which 1/3 of the fat is replaced by olestra. For objectives a-d, all subjects have completed assessment. For aims a) and b) the clinical chemistry laboratory analysis is completed and the database is near completion. We anticipate that the primary analysis will occur over the next 6-12 months with additional analyses to follow. For aim c) we have identified two key pathways affected by a high fat diet after developing an 18,861-gene RNA microarray. Three days of a high fat diet decreased mRNAs in skeletal muscle for a cluster of genes involved in glucose uptake and oxidation and increased transcription of a key inhibitor of glucose flux into the tricarboxylic acid cycle (PDHK4). To our knowledge, this is the first example of a coordinated negative feedback loop that is controlled by dietary fat at the level of transcription. We have termed this a RNA Randle effect. Second, these genes cluster with a second group of genes involved in energy metabolism. Recent publications in individuals with a positive family history of diabetes and in aging individuals demonstrate a defect in mitochondrial oxidative phosphorylation genes. These same genes were downregulated in healthy young volunteers fed a high fat diet suggesting a mechanism by which high fat diets might be involved in the genesis of obesity and the metabolic syndrome. Additional studies in cultured skeletal muscle cells from these same volunteers are in progress to determine the signaling and transcriptional pathways affected by high fat diets. Similarly, studies of interindividual differences in fat oxidation. For objective e), the data collection phase is completed. Six men and 2 women were recruited. Each received each of the three meals in a randomized order. Blood samples were analyzed for glucose, insulin, leptin, lipids and ghrelin. The data are currently being analyzed. Preliminary examination revealed NO metabolic differences between the 3 meals on any of the variables. For objective f), the protocol has been completed, IRB approval obtained, and recruiting has begun. The baked goods containing Olestra or normal dietary fats have been prepared. The first three or four participants will be recruited by mid-2004 and the remainder by the end of the year.

Impacts
There is currently an epidemic of obesity in the United States. Several predictors for the storage of body fat have been identified by Pennington investigators in past studies. Several questions remain to be answered regarding the fat storage syndrome and the adaptation to dietary fat. The studies in this project are designed to examine the effects of changing dietary fat on the metabolic and endocrine responses of healthy and overweight Americans.

Publications

  • Nguyen T, deJonge, L., Smith, S.R. and Bray, G.A. 2003. Chamber for indirect calorimetry with accurate measurement and time discrimination of metabolic plateaus of 20+ minutes, Medical and Biological Engineering and Computing. Med Biol Eng Comput 41:572-578.
  • Bray, G.A. 2003. Hunger. IN: Encyclopedia of Food and Culture S H. Katz (ed). New York: Charles Scribners Sons.
  • Bray, G.A. 2003. Obesity IN: Encyclopedia of Food and Culture, S.H. Katz (ed). New York: Charles Scribners Sons.
  • Bray, G.A. 2003. Foreword. IN: Treating and Preventing Obesity. An Evidence Based Review. Ostman J., Britton, M. and Jonsson, E. (eds). New York: Wiley.
  • Bray, G.A. and Bouchard, C. 2003. Handbook of Obesity: Etiology and Patholophysiology. New York: Marcel Dekker, 2nd ed, pp 1-1072.
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