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United States Department of Agriculture

Agricultural Research Service

Research Project: Linking Foods, Behavior and Metabolism to Promote a Healthy Body Weight

Location: Obesity and Metabolism Research Unit

2013 Annual Report

1a.Objectives (from AD-416):
Objective 1: Evaluate mediators of behavior change critical for adopting a healthy diet by investigating interrelationships between psychosocial stress, nutritional behavior and metabolism in humans and animal models. Objective 2: Determine how diet patterns, whole foods, and food components influence physiology and metabolic health by impacting eating- and neuro-behaviors, energy balance and substrate utilization, fitness, body weight and body composition in humans. Objective 3: Determine mechanisms underlying the regulation of body weight and disorders associated with obesity, by examining hormonal, neuronal, and metabolite pathways linking adipose and non-adipose tissues, and characterizing tissue-specific inflammation in humans, cells, and animal models. Objective 4: Determine the impact of dietary lipids on body weight, adiposity, and/or metabolic health indices by assessing their influence on lipoprotein-dependent trafficking of bioactive lipids to adipose and peripheral tissues, their effects on the regulation of metabolic homeostasis, and their interactions with distinct fatty acid desaturase/elongase activity phenotypes. Objective 5: Characterize the roles of cellular zinc in regulation of lipid metabolism, body fat mass, and fat distribution during postnatal development in genetically-modified animal models. Objective 6. Develop and validate phenotyping tools that classify and predict metabolic and body weight responses to dietary and physical activity interventions in individuals and populations.

1b.Approach (from AD-416):
We will use a multidisciplinary approach to test molecular, physiological, and metabolic responses to diets composed of whole foods or enriched with select macro- and micronutrients, determine how physical activity, stress, and genetic factors modify metabolism and responses to foods, identify important behavioral and psychosocial factors related to adopting the U.S. Dietary Guidelines, and determine basic physiological mechanisms underlying links between nutrition, physical activity, and metabolic health. Our work will use classical investigations of metabolism and energetics, along with metabolomic analyses, real-time determinations of brain activity in response to foods, and gene/protein expression determinations to investigate these questions, linking findings from these approaches to whole-organism phenotypes and human behavioral traits. Randomized controlled trials and analyses of samples from longitudinal observational studies will also be conducted. Important studies in animal and cell culture models will complement this work to gain a deeper understanding of underlying mechanisms and/or to obtain proof-of-concept information before designing and conducting human trials. Replacing: 5306-51530-016-00D (Laugero, Keim, Adams, Newman) and 5603-51530-014-00D (Huang). (2/09)

3.Progress Report:
Progress was made on all six objectives that fall under National Program 107, Human Nutrition. For Objective 1, data collected for a brain imaging study was analyzed. In subjects who reported a higher level of chronic psychological stress exposure, brain regions known to be involved with reward and emotion were activated upon visualization of highly palatable foods whereas areas associated with decision-making were deactivated, suggesting that in persons with chronic stress, there is increased risk for emotional eating and dietary habits inconsistent with the Dietary Guidelines. For Objective 2, subject enrollment for a study to identify barriers and benefits to increasing whole grain consumption was completed and lab analysis, including effects on gut microbiota is in progress. A study on breakfast eating, showed improved insulin sensitivity in response to a lunch meal if breakfast was eaten prior to the meal. For Objective 3, an intervention study designed to identify metabolite changes associated with improvements in physical fitness and weight loss in unhealthy obese persons was completed, and biomarkers related to glucose tolerance were discovered, some of which were derived from microbes inhabiting the gut. For Objective 4, omega-3 fatty acid-rich diets fed to hamsters increased these lipids and their metabolites in adipose and muscle tissues, and endocannabinoid profiles in peripheral tissues and plasma were altered by the diet lipid composition. Lipid profiles were analyzed from other dietary lipid interventions studies in mice, pigs, and humans. The lipid profiles of tissues and circulating lipoproteins were responsive to changing dietary lipid composition. Progress on Objective 5, included the discovery that a QTL (quantitative trait locus) exists in the mouse genome that influences body adiposity when mice are zinc deficient. Gene expressions of ten candidate genes in the QTL that have been shown to function in regulation of body adiposity were examined. Half of these genes displayed genotype-dependent and body-weight dependent differences in expression. For Objective 6, a retrospective analysis of a data from an omega-3 feeding study in African-Americans found that a habitual diet low in dark green vegetables reduced the incorporation of omega-3 fatty acids into red blood cells, and the subsequent triglyceride lowering and anti-inflammatory effects. This suggests that the health benefits of omega-3 fats in this population are largely dependent upon co-intake of specific vegetables, a finding that can impact public health messaging. Other studies toward Objective 6, involved comparisons of fat tissue from weight-matched healthy vs. unhealthy (Metabolic Syndrome or type 2 diabetes) women, which showed that weight-independent metabolic phenotypes in unhealthy obesity involve reductions in certain amino acid metabolic pathways and disruption of normal tissue architecture (extracellular matrix). Altogether, these results indicate that future public health considerations in obesity will be more effective if assessments do not solely focus on body weight.

1. Chronic stress alters brain responses to food images. ARS researchers in Davis, California, found that chronic stress may result in exaggerated reactivity to calorically-dense foods and food consumption beyond caloric need. Higher self-reported chronic stress in women was associated with eating more foods with high caloric density from a snack food buffet, abnormal stress hormone response to a mental challenge test, and an exaggerated activity in regions of the brain involving emotion, reward, and motivation when viewing pictures of high calorie foods. Also in the women reporting more stress, their brain scans showed reduced activity in the cognitive control regions. Thus, repeated stress exposure may alter the brain’s response to food in ways that increase emotional motivation for consuming high calorie foods and disable control over emotional overeating.

2. Protein and fat metabolism in diabetes. Type 2 diabetes (T2D) and conditions of pre-diabetes or insulin resistance are associated with perturbed metabolism of not just sugar, but also amino acids and fats. It has been proposed that elevations in certain blood amino acids provoke tissue systems that contribute to poor blood sugar control. However, ARS scientists in Davis, California, have shown that increased blood amino acids appear to be the result—and not a cause—of type 2 diabetes complications. This raises doubt about assertions that dietary protein should be limited in order to avoid T2D.

3. Metabolites affect effectiveness of insulin. In pre-diabetes and in the transition to frank type 2 diabetes (T2D), it is unclear what triggers the associated inflammation and tissue resistance to the blood sugar control hormone insulin. ARS scientists in Davis, California, discovered that metabolites accumulate under these conditions and can contribute to dampening insulin’s effects in muscle cells. These metabolites also promote inflammation. Thus, nutritional or other strategies to limit build-up of the metabolites (acylcarnitines) may thwart metabolic disturbance and help improve blood sugar control.

4. Decision-making ability and weight control. Obesity prevention through dietary restriction is difficult to achieve for some people, particularly for those who overeat in response to emotions or mood. Unsuccessful dieters may have reduced ability to inhibit or control emotional eating, which can result in dietary relapse. A study conducted by ARS scientists in Davis, California, showed for the first time, that those with greater amounts of diet-induced weight loss also displayed higher scores on a cognitive test of assessing self-control and strategic decision-making. The results suggest that differences in obesity prevention success may depend in part on person-to-person differences in higher brain cognitive pathways that influence or are altered by dieting and weight loss.

5. Biomarkers of liver health. Type 2 diabetes (T2D) often occurs with obesity, making it difficult to discriminate whether the metabolic complications arise from T2D or obesity. ARS scientists in Davis, California, evaluated plasma lipid and lipid mediator profiles in obese subjects with and without T2D. They found that plasma lipid markers typically associated with the development of fatty liver disease and altered liver fat metabolism were exacerbated in the diabetic subjects. These markers circulating in the bloodstream could be useful in predicting liver health in obese, diabetic persons.

6. Zinc and insulin resistance in muscle. The conditions of insulin resistance and prediabetes can progress to type 2 diabetes if no dietary or other intervention occurs. Using a mouse model of cellular zinc deficiency that lacks a specific zinc transporter, ARS scientists have demonstrated that cellular zinc is a key factor in maintaining normal metabolism in skeletal muscle, a tissue that consumes the majority (~80%) of body blood sugar. They discovered for the first time that when zinc levels are low in the skeletal muscle of these mice, lipid accumulates. Lipid accumulation and insulin resistance are associated in humans, but it is not yet known if lipid causes insulin resistance or if insulin resistance induces lipid accumulation in muscle. This discovery in mice with low zinc status supports the idea that lipid accumulation may directly contribute to insulin resistance.

7. Zinc and body fatness. Susceptibility to obesity and associated diseases often has a genetic component, but the genes involved remain to be fully catalogued. Using a mouse model that lacks a specific protein that transport zinc in the body, ARS researchers in Davis, California, identified a gene region on chromosome 7 that modifies body fatness and links body zinc status to body fatness. There are about 250 expressed genes located in this newly-identified region. Since this gene region was only manifested in mice lacking the zinc transporter, the results indicate that body zinc status has a direct effect on body fat accumulation. Discovery of a modifier gene of body fatness that is associated with cellular zinc levels helps provide a molecular basis for zinc function in regulation of body weight and adiposity.

8. Omega-3 fatty acids and body weight. The Dietary Guidelines for Americans include recommendations for the consumption of foods enriched in omega-3 fatty acids to reduce the risk of cardiovascular disease, but it is not known who benefits the most from this type of global recommendation. ARS scientists evaluated the efficacy of omega-3 fatty acid supplementation in healthy men. They showed that body weight, combined with measures of omega-3 status, influenced the magnitude of beneficial response of omega-3 fats related to cardiovascular health. Therefore body weight and baseline omega-3 status should be considered when future dietary recommendations for omega-3 consumption are proposed.

Review Publications
Bruins, M.J., Dane, A.D., Strassburg, K., Vreeken, R.J., Newman, J.W., Salem, Jr, N., Tyburczy, C., Brenna, J.T. 2013. Plasma oxylipin profiling identifies polyunsaturated vicinal diols as responsive to arachidonic acid and docosahexaenoic acid intake in growing piglets. Journal of Lipid Research. 54(6):1598-1607.

Witbracht, M., Van Loan, M.D., Adams, S.H., Keim, N.L., Laugero, K.D. 2012. Dairy food consumption and meal-induced cortisol response interact to influence weight loss in overweight women undergoing a 12-week meal-controlled weight loss intervention. Journal of Nutrition. 143(1):45-52.

Aaron, G., Keim, N.L., Drewnowski, A., Townsend, M. 2013. Estimating dietary costs of low-income women in California: A comparison of two approaches. American Journal of Clinical Nutrition. 97(4):835:841.

Huang, L., Tepaamorndech, S. 2013. The SLC30 family of zinc transporters – a review of current understanding of their biological and pathophysiological roles. European Journal of Applied Physiology. 34(2-3):548-560.

Strassburg, K., Pedersen, T.L., Huijbrechts, A.M., Kortekaas, K., Lindeman, J., Dane, A., Berger, R., Brenkman, A., Hankemeier, T., Van Duynhoven, J., Kalkhoven, E., Newman, J.W., Vreeken, R. 2012. Quantitative profiling of oxylipins through comprehensive lc-ms/ms analysis: Application in cardiac surgery. Analytical and Bioanalytical Chemistry. 404(5):1413-1426.

She, P., Olson, K.C., Kadota, Y., Inukai, A., Shimomura, Y., Hoppel, C., Adams, S.H., Kawamata, Y., Matsumoto, H., Sakai, R., Lang, C.H., Lynch, C.J. 2013. Leucine and protein metabolism in obese zucker rats. PLoS One. 8(3):e59443.

Millership, S., Ninkina, N., Guschina, I., Norton, J., Brambilla, R., Oort, P.J., Adams, S.H., Dennis, R.J., Voshol, P.J., Rochford, J.J., Buchman, V.L. 2012. Increased lipolysis and altered lipid homeostasis protect y-synuclein null mutant mice from diet-induced obesity . Proceedings of the National Academy of Sciences. 109(51):20943-20948.

Thomas, A.P., Dunn, T.N., Drayton, J.B., Oort, P.J., Adams, S.H. 2013. A dairy-based high calcium diet improves glucose homeostasis and reduces steatosis in the context of pre-existing obesity. Obesity. 21(3):E229-235.

Grapov, D., Adams, S.H., Pedersen, T.L., Garvey, W.T., Lok, K.H., Newman, J.W. 2012. Type 2 diabetes associated changes in the plasma non-esterified fatty acids, oxylipins and endocannabinoids. PLoS One. 7(11):e48852.

Sun, C., Alkhoury, K., Wang, Y.I., Foster, G.A., Radecke, C.E., Tam, K., Edwards, C.M., Facciotti, M.T., Armstrong, E.J., Knowlton, A.A., Newman, J.W., Passerini, A.G., Simon, S.I. 2012. IRF-1 and miRNA126 modulate inflammatory VCAM-1 expression in response to a high fat meal. Circulation Research. 111:1054-1064.

Pieper, J.R., Laugero, K.D. 2012. Preschool children with lower executive function may be more vulnerable to emotional-based eating in the absence of hunger. Appetite. 62:103-l09.

Last Modified: 4/20/2014
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