Source: AGRICULTURAL RESEARCH SERVICE submitted to
LINKING FOODS, BEHAVIOR AND METABOLISM TO PROMOTE A HEALTHY BODY WEIGHT
Sponsoring Institution
Agricultural Research Service/USDA
Project Status
TERMINATED
Funding Source
Reporting Frequency
Annual
Accession No.
0416498
Grant No.
(N/A)
Project No.
5306-51530-019-00D
Proposal No.
(N/A)
Multistate No.
(N/A)
Program Code
(N/A)
Project Start Date
Mar 16, 2009
Project End Date
Mar 15, 2014
Grant Year
(N/A)
Project Director
KEIM N L
Recipient Organization
AGRICULTURAL RESEARCH SERVICE
800 BUCHANAN ST, RM 2020
BERKELEY,CA 94710-1105
Performing Department
(N/A)
Non Technical Summary
(N/A)
Animal Health Component
(N/A)
Research Effort Categories
Basic
30%
Applied
60%
Developmental
10%
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
70260101010100%
Goals / Objectives
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.
Project Methods
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)

Progress 03/16/09 to 03/15/14

Outputs
Progress Report 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. 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. This is the final report for the project which has been replaced by 5306- 51530-022-00D, "Improving Public Health by Understanding Diversity in Diet, Body, and Brain Interactions". Please see the report for the new project for additional information. Substantial results were generated by the research team who completed human trials, studies with national/international collaborators, and animal model studies. Objective 1 examined the relationships between chronic and acute stress, the stress-hormone-regulating hypothalamic-pituitary-adrenal (HPA) axis, obesity-promoting metabolic changes, and food choices. In a primate model of chronic social stress, disturbances in fatty acid metabolism were uncovered that were linked to stress responsiveness, indicating that specific blood lipids (�fats�) may signal chronic psychological stress and open the door for assessment of blood biomarkers to track stress phenotypes in people. A study with mid-life women found that those who reported high levels of chronic stress and responded accordingly to a psychosocial stress test consumed significantly more calories from a highly palatable food (chocolate cake) offered in a snack buffet. Chronic stress in women aged 45 and older was related to more calories and fewer vegetables consumed at the buffet, stress-induced negative mood and food craving. These results show that women with a specific chronic stress signature are at increased risk for choosing palatable �comfort food.� Methodology was developed for a brain imaging study; in subjects with higher levels of chronic psychological stress, brain regions involved with reward and emotion were activated upon visualization of highly palatable foods, whereas decision-making areas were de-activated relative to lower-stress subjects. These results imply that, a history of chronic stress drives increased risk for emotional eating involving food choices inconsistent with the Dietary Guidelines. In objective 2, human studies focused on evaluating whole grains and soluble fibers, the relation of eating breakfast to metabolic health and satiety, and the impact of added sugar consumption on metabolic function. A study to examine consumer acceptance and behavior related to eating whole grains revealed that whole grain products were rated higher in liking, appearance, flavor, and texture than their refined grain counterparts. Exposure to whole grain foods for 6 weeks resulted in a positive shift in the association of whole grains and good taste, but this was not linked to behavior of increased whole grain consumption. To examine benefits of whole grains and other sources of dietary fiber on gut health, methods were developed to measure products of gut fermentation. Preliminary results indicate that subjects whose resident gut microbes produce methane exhibit better blood glucose control. Other studies examined the effect of breakfast eating on diet, appetite, and mitigation of the stress response. Comparing breakfast eaters to breakfast skippers, energy intake was not different, but diet quality and blood sugar control indices were better in breakfast eaters. Normal diurnal rhythms of cortisol, a stress hormone, were disrupted in subjects who skipped breakfast. Eating breakfast primed satiety hormones to reach at higher levels later in the day. Finally, studies in a collaboration with the University of California, Davis, found that even lower doses of high fructose corn syrup (HFCS) sweetened beverages (10% of calories) increased lipid risk factors for cardiovascular disease (CVD) in young adults after only 2 weeks. Objective 3 addressed the complex network of hormones, metabolites, and cellular factors that coordinate energy homeostasis, blood sugar control and inflammation. Two new proteins, Tusc5 & SNCG, were characterized with unusual expression in fat cells & peripheral neurons that sense temperature, pain, and other signals. It was found that the genes for these factors are targets of molecules that activate a metabolic pathway (PPARg) important to metabolic regulation, and seem to play a role in normal fat cell and neuron metabolism. Studies in mouse models (funded by the National Dairy Institute, Subordinate Project 5305-51530-019-56T) found that obesity, inflammation and blood sugar control could be dramatically improved by inclusion of dairy food, suggesting bioactives in dairy attenuate factors associated with metabolic disease. Additional studies in obese and overweight human subjects indicated that increased blood levels of certain amino acids and novel molecules were correlated with poor blood sugar control and inefficient fat combustion, providing new potential avenues for prognostic testing for type 2 diabetes risk. These studies, funded in part through subordinate rojects 5306-51530-019- 25R and 5306-51530-022-08I, identified specific fats that are higher in pre-diabetes and type 2 diabetes that increase inflammation and reduce the activity of the blood sugar regulating hormone insulin. Other blood metabolites derived from gut bacteria tracked metabolic health. Overall, Objective 3 studies provide new perspectives that point up the connectivity between diet, host health and the gut microflora, peripheral neurons, fat and other organs. This information should be important to design strategies to thwart metabolic diseases. In Objective 4, techniques were developed to isolate, separate and quantify lipids and their bioactive metabolites, providing the ability to investigate the functional impact of perturbed lipid metabolism as occurs in obesity and diabetes. Studies investigated how dietary fats influence lipid and lipid mediator profiles, distribution, and synthesis in plasma and tissue of healthy and obese models, including rodents, swine, and humans. Diets with different fat/carbohydrate or different omega-6/omega- 3 fatty acid ratios were fed to hamsters, and lipid profiles and gene expression were assessed in harvested tissues. The low fat diet increased liver lipid synthesis indices, and increased linoleate and alpha- linoleate derived epoxide and ketone content of adipose tissue. Omega-3 fatty acid-rich diets fed to hamsters increased these lipids and their bioactive metabolites in adipose and muscle, without substantial changes in pro-inflammatory omega-6-derived mediators. Extending these studies in humans, omega-3 fatty acid supplements were found to increase omega-3 signaling lipids uniquely within lipoprotein classes, i.e., VLDL and HDL. In humans on statin therapy to decrease LDL-cholesterol, omega-3 fatty acid consumption decreased triglycerides, while increasing lipoprotein content and tissue delivery of omega-3 lipid mediators, a new potential mechanism of action for these bioactive dietary components. In a retrospective case/control study of adults with or without acute coronary syndrome, red blood cells were analyzed, and lipid metabolic phenotypes associated with increased stearoyl-CoA desaturase and very long chain fatty acid synthesis activity had reduced risk of acute coronary syndrome, while metabotypes with higher polyunsaturated fatty acid synthesis activity were found more frequently in subjects with disease. Objective 5 characterized the roles of cellular zinc in regulation of lipid metabolism, body fat mass, and fat distribution. Using genetically- modified mice lacking a zinc transporter (Znt7 KO mice), Znt7 positively regulated insulin synthesis and secretion, consistent with low fasting insulin in Znt7 KO mice. Male Znt7 KO mice fed a high fat diet developed hyperinsulinemia and had impaired glucose intolerance due to downregulation of the insulin signaling pathway in muscle, resulting in decreased glucose uptake and insulin resistance. Znt7 KO mice had increased lipids (fat) and long chain fatty acid levels in muscle, a possible mechanism of insulin resistance that has also been implicated in humans. Znt7 KO mice were lean and weighed less than wild type mice. In genetic crosses with Znt KO mice, a significant site on chromosome 7 was found to associate with body weight and body fat. Several genes in this region have been identified, a significant step towards identifying novel modifier genes for weight and body adiposity potentially relevant to humans. Objective 6 assessed human variability in nutritionally relevant responses. A targeted lipidomic comparison of type 2 diabetics and non- diabetics discovered differences in vasodilatory epoxy fatty acids and immune-modulatory lipid ethanolamides (partly funded by NIH Award, Subordinate Project 5306-51530-019-25R). In a separate study, lipidomic profiling of atherosclerotic tissue provided empirical evidence of inflammation and tissue repair mechanisms in the impacted vascular wall. A retrospective analysis of 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 subsequent triglyceride lowering and anti-inflammatory effects. This suggests that the health benefits of omega-3 fats depends on co-intake of specific vegetables, a finding that can impact public health messaging. A study of the response to low versus high glycemic index foods found three unique phenotypic responses: 1) normal postprandial glucose clearance maintained by normal insulin & leptin responses; 2) subtle postprandial hyperinsulinemic response to maintain a normal postprandial glucose clearance; 3) subtle late phase hyperleptinemic response to maintain a normal postprandial glucose clearance. Finally, a metabolomic investigation of weight loss in response to caloric restriction identified low levels of sedentary behavior and low levels of light activity as key factors that associated with unique blood metabolite patterns tracking inter-individual weight loss efficacy (funded in part by the Dairy Research Institute, subordinate project 5306-51530-019-56T). Accomplishments 01 Chronic stress may alter the brain's response to calorically-dense foods and overeating. ARS scientists at Davis, California, found that higher self-reported chronic stress in women was associated with eating more high calorie foods from a snack food buffet, abnormal stress hormone (cortisol) 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. Reduced activity was observed in cognitive control regions of women reporting more stress. 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. These studies indicate that strategies that lower stress hold promise to elicit improved decision-making in terms of healthy eating behaviors. 02 Identifying metabolites associated with inefficient metabolism that trigger inflammation. Molecules called acylcarnitines are essential for lipid transport within cells. ARS scientists at Davis, California, discovered that the accumulation of acylcarnitines and by-products in blood and tissues is associated with inefficient metabolism (typical in people with type 2 diabetes and pre-diabetes), and this accumulation triggers inflammation. The research has also uncovered that high concentrations of acylcarnitines reduce the effectiveness of the blood sugar-controlling hormone insulin, in muscle. Since inflammation pathways are implicated in poor health outcomes, and insulin resistance is a hallmark risk factor for type 2 diabetes, interventions that improve metabolic efficiency and reduce acylcarnitine by-product accumulation (such as physical fitness and weight loss) should improve health. 03 Green vegetable intake may influence the efficacy of omega-3 fatty acid consumption. While health benefits of omega-3 fatty acid consumption have been well-documented, the efficacy of such dietary interventions varies considerably among individuals and the sources of this variance are poorly understood. ARS researchers at Davis, California, retrospectively found that a depressed response to omega-3 fatty acid supplementation was strongly associated with a habitual diet pattern which was low in dark green vegetable intake. This effect was reflected in clinically relevant changes in plasma triglycerides and the inhibition of immune cell inflammatory responses. These findings suggest an interaction between habitual diet and the efficacy of omega- 3 fatty acid intake, which may have fundamental impacts on dietary recommendations to reduce cardiovascular risk (i.e., targeting those who would benefit most from omega-3-rich foods). 04 New blood �self� and �non-self� metabolites that track metabolic health. ARS scientists in Davis, California, found that blood metabolite analyses (�metabolomics�) pointed to perturbations in lipid, protein, and sugar metabolism in obese insulin-resistant and diabetic states. Some altered blood metabolites also appeared to emanate from gut bacterial populations, highlighting the importance of non-self gut organisms and diet in driving systemic metabolism in obesity. These results suggest that blood metabolite signatures reflecting inefficient fat tissue amino acid and fat breakdown, and changes in the gut microbe environment, underlie health outcomes in response to diet and in persons at-risk for developing type 2 diabetes. A re-set of the gut microbes and tissue amino acid metabolic enzymes, i.e., through diet and weight loss, holds promise to prevent or dampen compromised metabolism seen in pre-diabetes and type 2 diabetes. 05 Breakfast and insulin action. Regular breakfast consumption is linked to better health outcomes across the population. The specific health benefits of eating breakfast have remained elusive. ARS scientists at Davis, California, found that individuals who skipped breakfast had indications of reduced insulin sensitivity because they needed higher insulin levels to keep blood glucose in check following lunch and afternoon snacks compared to their breakfast-eating counterparts. This demonstrates that habitually omitting breakfast may compromise insulin action, a risk factor for type 2 diabetes. 06 Food choices in children. Poor development of decision-making skills early in life may increase risk for emotional-based food choices later in life. In preschoolers, greater palatable snack food intake was associated with poor inhibitory control. Eating in the absence of hunger was also associated with emotional arousal measured by skin conductance. Thus, even in very young children a shift away from executive to more emotional decision-making may promote excess calorie consumption. 07 Magnitude of weight loss in response to caloric restriction may be linked to executive brain function (decision-making). Obesity has serious mental and physical health implications and is a major global concern. Moderate losses in body weight can significantly improve health, but dietary relapse and weight regain are common. However, some persons are more successful than others at losing and keeping off weight lost by dieting. The reasons for this are multi-factorial, but growing evidence suggests that brain regions critical to decision- making may be linked to the magnitude and durability of dietary and body weight changes. ARS researchers in Davis, California, discovered that person-to-person differences in weight loss were inversely associated with salivary cortisol concentrations (a stress index) and decision-making functions characterized by greater risk taking in obese women who underwent a weight loss regimen. Thus, higher decision making functions and stress neuroendocrine pathways can influence or be altered by the process of dieting, and these correspond to the amount of weight loss achieved. 08 A better way to assess food preferences. In research, self-reports of food preferences can be biased, particularly if participants think investigators are anticipating certain responses. ARS scientists in Davis, California, programmed a paired food comparison test to evaluate preferences for food categories varying along the dimensions of high/ low fat content and sweet/savory taste. When applied to a longitudinal study that provided whole or refined grain products to participants, those consuming refined grain products increased their preferences for foods in the high-fat sweet category, whereas those receiving whole grain products did not. Exposure to refined grain foods may have altered preferences so that less healthy foods generally high in fat, sugar, and refined carbohydrates were favored. But, more importantly, this work demonstrates that use of computerized tests such as the paired-food paradigm can uncover preferences for nutritionally less desirable foods that maybe more difficult to detect with a self-report questionnaire. 09 Peripheral sensory neurons and metabolism. We sense temperature, pain, and one�s place in 3D space via signals generated by peripheral sensory nerves, making this nerve network a critical player in normal function and health. Yet, little is understood about the impact of metabolic health in non-diabetics on the peripheral neurons, or their roles in regulating metabolism. ARS researchers in Davis, California, discovered that a metabolite-sensitive gene-regulating protein termed peroxisome proliferator activated receptor gamma (PPARg), master controller of fat metabolism and fat cell (adipocyte) growth and function, controls expression of unique proteins termed Tusc5 and synuclein-gamma that are highly-expressed in fat and peripheral sensory neurons. These unique findings illustrate that the body�s metabolism might be controlled in part through factors in the sensory nerves, opening the door for new interventions that target these cells to improve metabolic health. 10 Natural changes in the gut�s bacteria associate with changes in liver and kidney function. It is now appreciated that the specific bacterial �blooms� in the gut (the gut microbiome) are quite sensitive to diet, and play a critical role in modifying the host organism�s health. Increasingly, metabolic and inflammatory health (blood sugar control, weight, tissue inflammation) have been linked to diet-associated gut microbe alterations. In studying how diet impacts gut microbes and their signals, ARS researchers in Davis, California, discovered that dietary resistant starch markedly changed the liver metabolome (the catalog of hundreds of metabolites at once in the tissue) in mice, leading to lower liver amino acid metabolism indices. In collaborative studies with the University of California, Irvine, resistant starch also rescued much of the inflammation and pathology associated with chronic kidney disease in a rat model. The studies highlight that dietary intervention with resistant starch can readily change the gut bacteria, in turn improving host health and nitrogen balance, possibly providing a cost-effective non-pharmaceutical means to prevent or reverse disease progression. 11 Development of analytical method to measure lipid composition within intracellular lipid droplets. Despite the importance of lipid droplets in physiology, it remains difficult to measure their chemical composition. Researchers at the University of California, Davis, in collaboration with ARS scientists in Davis, California, validated a novel analytical technique to measure the fatty acid composition within single cellular lipid droplets using infra-red Raman spectroscopy. The composition of individual droplets was found to closely approximate the average fatty acid composition of cells. Moreover, the assay was able to discriminate other subcellular structures (organelles) based on their lipid profiles. This technological advancement provides novel tools to investigate metabolism and the cellular sub-structural level. 12 Lipid profiling following omega-3 intake identifies plasma EPA metabolites as potent predictors of atherosclerosis prevention. The mechanisms by which omega-3 consumption can reduce atherosclerotic risk are poorly understood, and biomarkers of clinical efficacy are presently unavailable. A collaboration between ARS scientists in Davis, California, and researchers in France (INRA/Universit� d'Auvergne, Clermont-Ferrand; Universit� de Montpellier; University of Franche Comt�, Besan�on; CNRS/INRA/Universit� de Bourgogne, Dijon) found that feeding docosahexenoic acid (DHA) to atherosclerosis-prone mice, not only reduced atherosclerosis in a dose-dependent manner, but also increased concentrations of eicosapentaenoic acid (EPA) metabolites in a similar fashion. This study suggests that EPA-metabolism may be directly responsible for the atherosclerotic risk reduction associated with omega-3 fatty acid consumption. This finding supports further evaluation of dietary recommendations associated with omega-3 fatty acids which considers the specific composition and source of consumed lipids. Not all omega-3s are created equal. 13 Identification of quantitative trait loci (QTLs) that influence body weight gain in Znt7 knockout mice. A direct link between body weight regulation/adiposity and zinc homeostasis is lacking, but ARS researchers in Davis, California, recently discovered that mice lacking the zinc transporter protein Znt7 are leaner even when fed a high fat diet. Quantitative trait loci (QTLs) are a valuable resource to identify candidate genes responsible for the lean characteristics of Znt7 knockout mice. QTLs are chromosomal regions statistically associated with a particular characteristic. A QTL mapping approach in the knockout mice revealed a chromosomal region associated with body weight and body fat. This study is the first to identify genetic regions that associate zinc metabolism to body weight regulation, in support of a role for proper zinc nutrition and cellular zinc handling in maintaining body weight and metabolic health. Specific body fat- associated genes stemming from these studies (i.e., the candidate Adamts17) can ultimately be evaluated in human populations to determine potential gene-environment links to obesity.

Impacts
(N/A)

Publications

  • Mostaedi Md, R., Lackey, D.E., Adams, S.H., Dada, S.A., Hoda, Z.A., Ali Md, M. 2014. Prevalence of undiagnosed and inadequately treated type 2 diabetes mellitus, hyperension, and dyslipidemia in morbidly obese patients who present for bariatric surgery. Obesity Surgery. 24:927-935. DOI:10.1007/S11695-014-1196-Z.
  • Kadota, Y., Toyoda, T., Kitaura, Y., Adams, S.H., Shimomura, Y. 2013. Regulation of hepatic branched-chain alpha-keto acid dehydrogenase complex in rats fed a high-fat diet. Obesity Research & Clinical Practice. 7:e439- e444. DOI: 10.101016/j.orcp.2013.07.003.
  • Lackey, D.E., Burk, D.H., Ali, M.R., Mostaedi, R., Smith, W., Park, J., Scherer, P.E., Seay, S., Mccoin, C.S., Bonaldo, P., Adams, S.H. 2013. Contributions of adipose tissue architectural and tensile properties toward defining healthy and unhealthy obesity. American Journal of Physiology - Endocrinology and Metabolism. 306:E233-E246. DOI: 10.1152/ ajpendo.00476.2013.
  • Aguer, C., Feihn, O., Seifert, E.L., Bezaire, V., Meissen, J., Daniels, A., Scott, K., Renaud, J., Padilla, M., Bickel, D., Dysart, M., Adams, S.H., Harper, M. 2013. Muscle UCP3 overexpression mimics endurance training and reduces circulating biomarkers of incomplete beta-oxidation. Journal of Federation of American Societies for Experimental Biology. 27:4213-4225.
  • Campbell, C., Grapov, D., Fiehn, O., Chandler, C.J., Burnett, D.J., Souza, E.C., Casazza, G.A., Gustafson, M.B., Keim, N.L., Newman, J.W., Hunter, G. R., Fernandez, J.R., W. Timothy, G., Harper, M., Hoppel, C.L., Meissen, J. K., Takeuchi, K., Adams, S.H. 2014. Improved metabolic health alters host metabolism in parallel with changes in systemic xeno-metabolites of gut origin. PLoS One. 9(1):e84260. DOI: 10.1371/journal.pone.0084260.


Progress 10/01/12 to 09/30/13

Outputs
Progress Report 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. 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) 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. Accomplishments 01 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. 02 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. 03 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. 04 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. 05 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. 06 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. 07 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. 08 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.

Impacts
(N/A)

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.


Progress 10/01/11 to 09/30/12

Outputs
Progress Report 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. 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. 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 de-activated. These new results imply that, in persons with a history of chronic stress, there is an increased risk for emotional eating and dietary habits inconsistent with the Dietary Guidelines. For Objective 2, a study to identify barriers to increasing whole grain consumption continued and methods to distinguish liking (taste acceptability) from wanting (hedonic desire) of specific food products were employed. Data collection continued for a study of the effect of eating breakfast on food choices, satiety, and stress, and progress was made to examine the influence of sex steroids in modulating: i) weight and body composition changes in response to a physical activity intervention and ii) lipid responses to different doses of sugar-sweetened beverages. For objective 3, new methods were validated that provide a visual, biochemical, and molecular snapshot of healthy vs. unhealthy fat tissue in humans, which holds promise to identify those nutritional and genetic factors leading to poor metabolic health seen in many obese persons. In addition, metabolite profiling of blood in unhealthy obese persons was monitored as a diet and fitness regimen improved their metabolism, and unique markers of better health were identified. For objective 4, diets with different omega- 6/omega-3 fatty acid ratios and/or fat content were fed to hamsters. With a low fat diet, synthesis of lipids increased in the liver, and circulating metabolite markers indicative of this synthetic process were found. Adipose tissue triglycerides were enriched in eighteen carbon epoxides and ketones. In humans on statin therapy to decrease LDL cholesterol, omega-3 fatty acid supplementation decreased triglyceride levels, while increasing lipoprotein content and thus tissue delivery of omega-3 lipid mediators. VLDL and HDL were the most impacted. Progress on objective 5 included the discovery that Znt7 knockout mice (lacking a key zinc transporter) fed a high fat diet had reduced basal blood insulin levels and were diabetic. Over-expression of ZnT7 protein in muscles increased glucose uptake up to 2.0-fold. Also, a candidate region in a chromosome that is associated with body fat was identified in mice, and genes that are responsible for the adiposity differences are currently being sought. 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. Accomplishments 01 Unique neural-adipocyte genes. Synuclein gamma (SNCG) is a factor uniquely expressed in both fat cells and peripheral neurons that sense temperature, pain, and other signals. In collaborative work with ARS scientists, it was discovered that mice lacking SNCG display an altered metabolic response to high-fat diet-induced obesity. This suggests that some lipid-modifying, obesity-regulated genes found in fat cells, also present in peripheral nerves, could integrate environmental and dietary cues with the brain. This integration is critical to establishing metabolic health through its impact on whole-body physiology. 02 Intermediary metabolism of sugar & fats. Blood metabolite analyses pointed to perturbed amino acid metabolism in obese insulin-resistant an diabetic states. Also, enzymes associated with select amino acid breakdo were found to be significantly reduced in the fat of obese individuals. Some protein-derived blood metabolites tracked status of gut bacterial populations, highlighting the importance of non-self gut organisms and diet in driving systemic metabolism of amino acids in the obese state. This suggests that inefficient fat tissue amino acid breakdown for energ and changes in the gut microbe signature, underlie health phenotypes in response to diet. 03 Food choices in children. Poor development of decision-making skills early in life may increase risk for emotional-based food choices later i life. In preschoolers, greater palatable snack food intake was associate with poor inhibitory control. Eating in the absence of hunger was also associated with emotional arousal measured by skin conductance and salivary hormones. Thus, even in very young children a shift from executive to more emotional decision-making may promote excess calorie consumption. 04 Breakfast and insulin action. Regular breakfast consumption is linked t better health outcomes across the population. The specific health benefi of eating breakfast have remained elusive. It was found that individuals who skipped breakfast consistently were more insulin-resistant than thei breakfast-eating counterparts. This demonstrates that habitually omittin breakfast is related to compromised insulin action, a risk factor for ty 2 diabetes and impaired blood sugar regulation. 05 Omega-3 fatty acid recommendations. A diet rich in long chain omega-3 fatty acids is associated with reduced risk for cardiovascular disease, and recommended intake of fatty fish are based on this health benefit. T efficiency of omega-3 fatty acid consumption in regulating changes in beneficial lipids in blood components were found to decrease as a person omega-3 fatty acid status reached the levels associated with this health benefit. Based on the small study performed, current dietary recommendations appear to be in the right range to maintain a healthful omega-3 status for an average sized individual. However, individual recommendations would be improved by accounting for differences in body weight. 06 Development of bioinformatics tool. New technologies generate a large amount of information about physiological functions, genetics, and metabolism. High information content data analysis is a critical compone of modern biological research. A new open source software package was developed allowing access to the statistical power of R within a user- friendly Microsoft Excel environment. The software has been made free to download on the internet and has been accessed over 2,000 times by the public. 07 Lipid phenotyping to assess metabolic health. Obesity and type 2 diabet are often coincident conditions making the segregation of their metaboli consequences difficult. In a study comparing overweight African-American women with and without type 2 diabetes, it was discovered that independe of weight, diabetes elevated blood plasma free fatty acids, increased markers of hepatic lipogenesis, decreased markers of very long chain fat acids synthesis and altered specific classes of endocannabinoid metabolites. These findings demonstrate the usefulness of �lipidomics� which involves the analysis of a broad spectrum of lipid-soluble compoun circulating in blood. The application of �lipidomics� provides a means t directly assess the metabolic health of overweight individuals, going beyond the traditional determination of blood glucose alone. 08 Zinc and blood glucose control. Although type 2 diabetes is often associated with obesity, it can occur in lean subjects. Possible links t diabetes in lean individuals may be poor nutritional status, including imbalanced micronutrient metabolism. A mouse model was developed that lacks a key zinc transporter, and this led to poor blood sugar control i the mice despite that they remained lean on a high fat diet. The study revealed that zinc, an essential micronutrient, is an important player i maintaining normal secretion and function of the blood glucose-regulatin hormone insulin. 09 Zinc and glucose uptake in muscle. Muscle tissue requires a constant source of energy, including glucose, to function optimally. Micronutrien status may impinge upon pathways involved in tissue glucose uptake. A ra skeletal muscle cell line with enhanced zinc transporter proteins was developed to test this concept. The results demonstrated that the zinc transporter ZnT7 has an insulin-sensitizing effect leading to increased glucose uptake in muscle.

Impacts
(N/A)

Publications

  • Keenan, A.H., Pedersen, T.L., Fillaus, K., Larson, M.K., Shearer, G.C., Newman, J.W. 2012. Basal omega-3 fatty acid status affects fatty acid and oxylipin responses to high-dose n3-HUFA in healthy volunteers. Journal of Lipid Research. doi: 10.1194.
  • Adams, S.H. 2011. Emerging perspectives on essential amino acid metabolism in obesity and the insulin-resistant states 1,2. Advances in Nutrition. doi:10.3945.
  • Laugero, K.D., Tryon, M.S. 2011. Stress and food intake: What's the deal with your meal?. CAB Reviews: Perspectives in Agriculture, Veterinary Science, Nutrition and Natural Resources. doi: 10.1079/PAVSNNR20116034.
  • Krishnan, S., Newman, J.W., Hembrooke, T.A., Keim, N.L. 2012. Variation in metabolic responses to meal challenges differing in glycemic index in healthy women: Is it meaningful?. Journal of Nutrition and Metabolism. 9(1) :26.
  • Cox, C., Stanhope, K.L., Schwarz, J.M., Graham, J.L., Havel, P.J., Keim, N. L. 2011. Consumption of fructose-sweetened beverages for 10 weeks reduces net fat oxidation and energy expenditure in overweight/obese men and women. American Journal of Clinical Nutrition. Eur J Clin Nutr. 2012 Feb;66(2) :201-8.
  • Banna, J.C., Keim, N.L., Townsend, M.S. 2011. Assessing face validity of a physical activity questionnaire for Spanish-speaking women in California. Journal of Extension. Vol.49:5.
  • Thomas, A.P., Dunn, T.N., Drayton, J.B., Oort, P.J., Adams, S.H. 2012. A high calcium diet containing nonfat dry milk reduces weight gain and associated adipose tissue inflammation in diet-induced obsed mice when comparated to high calcium alone. Nutrition and Metabolism. 9:3.
  • Hirahatake, K.M., Meissen, J., Fiehn, O., Adams, S.H. 2011. Comparative effects of fructose and glucose on lipogenic gene expression and intermediary metabolism in HepG2 liver cells. PLoS One. 10.1371.
  • Viscarra, J.A., Vazquez-Medina, J.P., Rodriguez, R., Champagne, C.D., Adams, S.H., Crocker, D.E., Ortiz, R.M. 2012. Decreased expression of adipose CD36 and FATP1 are associated with increased plasma nonesterified fatty acids during prolonged fasting in northern elephant seal pups (Mirounga angustirostris) . Experimental Biology. 215(Pt 14):2455-64.
  • Huang, S., Rutkowsky, J.M., Snodgrass, R.G., Ono-Moore, K., Schneider, D.A. , Newman, J.W., Adams, S.H., Hwang, D.H. 2012. Saturated fatty acids activate TLR-mediated pro-inflammatory signaling pathways. Journal of Lipid Research. Epublished. DOI: 10.1194/jlr.D029546.
  • Grapov, D., Newman, J.W. 2012. imDEV: a graphical user interface to R multivariate analysis tools in Microsoft Excel. Oxford University Press. doi:10.1093.


Progress 10/01/10 to 09/30/11

Outputs
Progress Report 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. 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. Progress was made on all six objectives that fall under National Program 107, Human Nutrition. For Objective 1A a study on psychosocial stress was completed. For Objective 1B methodology was developed for a brain imaging study while doing tasks involving food choice under stressful and non-stressful conditions. To address Objective 2A, a study of gut health benefits of whole grains in humans, methods to measure end products of gut fermentation were developed. For Objective 2B data collection continued for a study of breakfast eating, dietary choices & stress. Methods were developed to examine the role of sex steroids in modulating the lipid response to different doses of sugar-sweetened beverages, an ongoing study for Objective 2C. Studies at the cellular level outlined in Objective 3A yielded the discovery that SNCG is expressed in peripheral neurons sensing temperature/pain and is active in PPARg- induced metabolic changes, suggesting that nutrition affects nerves that integrate environmental cues with the brain. For Objective 3B markers of immune cells (macrophages) in body fat tracked body weight in mice becoming obese on a high fat diet, the first report highlighting the role of immune cells in fat tissue growth for energy storage. A human study comparing metabolites of type 2 diabetics and non-diabetics was completed for Objective 3C, and results suggest that amino acid metabolism is impaired in diabetes, possibly contributing to inefficient tissue metabolism and accumulation of inflammatory by-products. For Objective 4A, a diet with different omega-6/omega-3 fatty acid ratios were fed to hamsters, and lipid profiles and gene expression were assessed in harvested tissues. In humans, analysis of ~400 plasma samples showed that omega-3 fatty acid supplements increased omega-3 signaling lipids that were distributed uniquely among different lipoprotein classes. For Objective 4B red blood cells from a retrospective case/control study of adults with or without acute coronary syndrome were analyzed, and novel lipid metabolism phenotypes were found more frequently in subjects with disease. For Objective 5A we discovered that insulin production & secretion is influenced by ZnT7 expression in pancreatic beta-cells. For Objective 5B we established pancreatic beta-cell lines over-expressing Glut4-HA & ZnT7 or ZnT7 alone. ZnT7 overexpression did not affect endogenous Glut4 expression. Glut4-HA was localized in Golgi network and recycling endosomes in the absence of insulin; upon insulin stimulation, Glut4-HA was recruited on to cytoplasmic membrane of L6 cells over- expressing Glut4-HA and ZnT7. In studies addressing Objective 5C, abnormal cellular zinc homeostasis had large effects on epididymal and retroperitoneal fat mass that were associated with 3 chromosomes in mice. For Objective 6 a targeted lipidomic comparison of type 2 diabetics and non-diabetics was completed and differences in vasodilatory epoxy fatty acids and immunomodulatory lipid ethanolamides were found. In a separate study, lipidomic profiling of atherosclerotic tissue provided empirical evidence of inflammation and tissue repair mechanisms in the impacted vascular wall. Accomplishments 01 Magnitude of weight loss in response to caloric restriction may be linke to executive brain function (decision making). Obesity has serious ment and physical health implications and is a major global concern. Moderat losses in body weight can significantly improve health, but dietary relapse and weight regain are common. However, some persons are more successful than others at losing and keeping off weight lost by dieting. The reasons for this are multi-factorial, but growing evidence suggests that brain regions critical to decision making may be linked to the magnitude and durability of dietary and body weight changes. We discovered that person-to-person differences in weight loss were inverse associated with salivary cortisol concentrations and decision making functions characterized by greater risk taking in obese women who underwent a weight loss regimen. Thus, higher decision making functions and stress neuroendocrine pathways can influence or be altered by the process of dieting, and these correspond to the amount of weight loss achieved. 02 Compositional changes of specific lipid fatty acids may form new functional markers of chronic psychological stress. Psychological stres and the neuroendocrine reaction to stress are associated with mental and physical diseases, such as obesity and depression. However, the respons to psychological stress varies from person to person, and this inter- individual variation in the stress response may contribute to difference in disease vulnerability. The physiological basis for differences in stress reactivity and disease remains unknown. Through the application o lipidomics, WHNRC scientists discovered that pre-existing differences in the omega-3:omega-6 composition of circulating triglycerides predicted a blunted neuroendocrine (cortisol) response to acute psychological stress However, this result was specific to subjects undergoing chronic psychological stress, which was also associated with alterations in othe specific fatty acid metabolites. Our results support the notion that th association between a dysfunctional stress response and stress related diseases such as depression may be functionally linked by shifts in or p existing abnormalities in fatty acid metabolism. 03 Dietary trans fatty acids impact blood lipids and fat accumulation. Dietary trans fatty acids produced by the partial hydrogenation of vegetable oils have negative effects on blood lipid profiles, and increa fat accumulation around the internal organs and within the liver. In 200 Denmark introduced legislation to reduce daily consumption of trans fats to less than 1 g per day, dramatically lower than in other countries. In this low trans fat exposed population, we found that increasing dietary consumption of trans fats to about 16 g per day for 16 weeks greatly increased blood lipid markers of cardiovascular risk, but did not produc a definitive change in either abdominal fat or liver fat deposition. The findings support limiting consumption of hydrogenated vegetable oils to reduce cardiovascular risk. However, we found that exposure to high tran fat levels for 16 weeks appears to have only mild effects on the accumulation of body fat in clinically healthy individuals. 04 Technological advances have the ability to increase our understanding of health and disease. Modern analytical chemistry practices are rapidly expanding our knowledge regarding the chemical composition of blood and other body fluids used routinely to assess health status. In a coordinated study among 9 institutions in Canada and the USA, an array o modern techniques was applied to the analysis of human serum and plasma that greatly enhanced our knowledge of normal human blood components, while assessing the strengths and weaknesses of the applied technologica platforms. This study produced a complete set of 4229 confirmed and highly probable soluble constituents in human blood, their concentration related literature references and links to their known disease associations which were made freely available through the internet at http://www.serummetabolome.ca. This information constitutes a powerful comparative resource for biomedical researchers. 05 Vitamin B12 status is an important factor in the assessment of health in the old and very young. Serum concentrations of methylmalonic acid are broadly used biomarker of vitamin B12 status. We have carefully optimiz an analytical method for methylmalonic acid quantification using liquid chromatography and mass spectrometry. This method reduced the amount of sample required for the assay from 1 mL to a maximum of 25 �L. The reported method is especially useful for studies of functional B12 statu in sample-limited experiments including investigations of nutritional status in newborns, making some such studies possible for the first time 06 A diet based on the U.S. Dietary Guidelines reduces chronic disease risk In obese sedentary women eating a U.S. Dietary Guideline-based diet for just several days, the blood level of insulin, the hormone controlling blood sugar, was markedly reduced and in many cases normalized. This study is one of the first to show that within days, consuming a nutritio diet can significantly improve hyperinsulinemia, a major diabetes risk factor, even in the absence of weight change and challenges existing perspectives that longer-term interventions including diet, physical activity and the resulting weight loss (e.g. the Diabetes Prevention Program studies) are required to thwart metabolic disease. These result are remarkable in that they indicate that choosing a diet with high nutrient density and low energy density has the promise to very rapidly improve health in people who are at-risk for diabetes. Since setting short-term, food-based goals without weight loss is quite achievable, su an approach has potential to yield significant health care cost savings. 07 Acylcarnitines are associated with inefficient metabolism. Molecules called acylcarnitines are essential for lipid transport within cells. WHNRC scientists discovered that the accumulation of acylcarnitines and byproducts in blood and tissues is associated with inefficient metabolis (typical in people with type 2 diabetes, pre-diabetes, and obesity), and this accumulation triggers inflammation. Since inflammation pathways are implicated in poor health outcomes, interventions that improve metabolic efficiency and reduce acylcarnitine by-product accumulation should impro health. Initial evidence suggests that dietary protein quality may elici tissue-level changes in lipid transport that promote metabolic efficienc and thus such dietary change holds promise to reduce metabolic complications or development of diabetes. 08 Dietary lipids impact circulating bioactive metabolites. The ingestion omega-3 fatty acids enriched lipoprotein particle concentrations of long chain omega-3 fatty acids, and an array of their oxygenated metabolites, while reducing levels of some corresponding omega-6 fatty acids. Changes in plasma were best reflected in very low density lipoprotein particles. Treatment-associated changes in vascular endothelial function were weakl correlated with changes in concentrations of omega-3 fatty acid epoxides and alcohols in low and high density lipoprotein fractions. This finding shows that dietary lipids can impact bioactive metabolites in circulatio which may be involved in the beneficial effects of diets rich in these materials.

Impacts
(N/A)

Publications

  • Purnell, J.Q., Klopfenstein, B.A., Stevens, A.A., Havel, P.J., Adams, S.H., Dunn, T.N., Krisky, C., Rooney, W.D. 2011. Brain fMRI response to glucose and fructose infusions in humans. Diabetes Obesity and Metabolism. 13(3) :229-34.
  • Fiehn, O., Garvey, W., Newman, J.W., Lok, K.H., Hoppel, C.L., Adams, S.H. 2010. Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non- Diabetic and Type 2 Diabetic Obese African-American Women. PLoS One. Vol. 5(12): e15234.
  • Laugero, K.D., Falcon, L.M., Tucker, K.L. 2011. Relationship between perceived stress and dietary and activity patterns in older adults participating in the Boston Puerto Rican Health Study. Appetite. 56:194- 204.
  • Gertow, K., Nobili, E., Folkersen, L., Newman, J.W., Pedersen, T.L., Swedenborg, J., Paulsson-Berne, G., Kuhn, H., Hedin, U., Wheelock, C.E., Hansson, G.K., Haeggstrom, J.Z., Gabrielsen, A. 2011. 12- and 15- lipoxygenases in human carotid atherosclerotic lesions: Associations with cerebrovascular symptoms. Atherosclerosis. 215:411-416.
  • Laugero, K.D., Smilowitz, J.T., German, J.B., Jarcho, M.R., Mendoza, S.P., Bales, K.L. 2011. Plasma omega 3 polyunsaturated fatty acid status and monounsaturated fatty acids are altered by chronic social stress and predict endocrine responses to acute stress in titi monkeys. Prostaglandins Leukotrienes and Essential Fatty Acids. 84(3-4):71-8.
  • Shearer, G.C., Harris, W.S., Pedersen, T.L., Newman, J.W. 2010. DETECTION OF OMEGA-3 OXYLIPINS IN HUMAN PLASMA AND RESPONSE TO TREATMENT WITH OMEGA- 3 ACID ETHYL ESTERS. Journal of Lipid Research. 51(8):2074-81.
  • Kim, S., Andaya, C.B., Newman, J.W., Goyal, S.S., Tai, T. 2008. ISOLATION AND CHARACTERIZATION OF A LOW PHYTIC ACID RICE MUTANT REVEALS A MUTATION IN THE RICE ORTHOLOGUE OF MAIZE MIK. Journal of Theoretical and Applied Genetics. 117(8):1291-301.
  • 2011. Food science challenge: Translating the dietary guidelines for americans to bring about real behavior change. Journal of Food Science. 76:R29-37.
  • Rowe, S., Alexander, N., Almeida, N., Black, R., Burns, R., Bush, L., Crawford, P., Keim, N.L., Kris-Etherton, P., Weaver, C. 2011. Translating the Dietary Guidelines for Americans 2010 to Bring About Real Behavior Change. Journal of American Dietetic Association. 111(1):28-39.
  • Laugero, K.D., Falcon, L.M., Tucker, K.L. 2010. Associations Between Life Stress and Patterns of Food Intake and Physical Activity in the Boston Puerto Rican Health Study. American Journal of Clinical Nutrition. 56(1) :194-204.
  • Stumbo, P.J., Weiss, R., Newman, J.W., Pennington, J.A., Tucker, K.L., Wiesenfield, P., Illner, A., Klurfeld, D.M., Kaput, J. 2010. Web-enabled and improved software tools and data are needed to measure nutrient intakes and physical activity for personalized health research. Journal of Nutrition. 140:2104-2115.
  • Psychogios, N., Hau, D.D., Peng, J., Guo, A., Mandal, R., Bouatra, S., Sinelnikov, I., Krishnamurthy, R., Eisner, R., Gautam, B., Young, N., Xia, J., Knox, C., Dong, E., Huang, P., Hollander, Z., Pedersen, T.L., Smith, S. R., Bamforth, F., Greiner, R., Mcmanus, B., Newman, J.W., Goodfriend, T., Wishart, D.S. 2011. THE HUMAN SERUM METABOLOME. PLoS One. 6(2): e16957.
  • Thomas, A.P., Dunn, T.N., Oort, P.J., Grino, M., Adams, S.H. 2011. Inflammatory phenotyping identifies CD11d as a gene markedly induced in white adipose tissue in obesity. Journal of Nutrition. 1172-1180.
  • Pedersen, T.L., Keyes, W.R., Shahab-Ferdows, S., Allen, L.H., Newman, J.W. 2011. An Optimized Method for Measuring Methylmalonic Acid in Low Volumes of Serum Using UPLC-MS/MS. Journal of Chromatography. B. 879, 1502-6.
  • Stanhope, K., Griffin, S.C., Bremer, A.A., Schaefer, E., Natkajima, K., Schwarz, J.M., Beysen, C., Berglund, L., Keim, N.L., Havel, P.J. 2011. METABOLIC RESPONSES TO PROLONGED CONSUMPTION OF GLUCOSE- AND FRUCTOSE- SWEETENED BEVERAGES ARE NOT ASSOCIATED WITH POSTPRANDIAL OR 24-HOUR GLUCOSE AND INSULIN EXCURSIONS. American Journal of Clinical Nutrition. 94:112-119.
  • Witbracht, M.G., Laugero, K.D., Van Loan, M.D., Adams, S.H., Keim, N.L. 2011. PERFORMANCE ON THE IOWA GAMBLING TASK IS RELATED TO MAGNITUDE OF WEIGHT LOSS AND SALIVARY CORTISOL IN A DIET-INDUCED WEIGHT LOSS INTERVENTION IN OVERWEIGHT WOMEN. Physiology and Behavior. 10.1016/j. physbeh.2011.04.035.


Progress 10/01/09 to 09/30/10

Outputs
Progress Report 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. 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) Psychosocial Stress: 35 out of targeted 40 human subjects have enrolled in the study, & data collection is in progress. Stress-reactivity & Brain Imaging: Methodology was developed & successfully piloted. Recruitment & enrollment are in progress; 15 subjects have enrolled, & brain imaging tasks have been completed for 6 subjects. Titi monkey model: Completed study, samples assayed, & data were statistically analyzed. A manuscript describing the results has been submitted to Psychoneuroendocrinology. Whole Grains: Intervention study examining consumer behavior & health benefits associated with whole grain products was initiated; enrollment of subjects is ongoing. Breakfast & Metabolism: Extramural funding was obtained to study the effect of breakfast eating on dietary choices & mitigation of the stress response. 22 volunteers have enrolled; data collection is in progress. Added Sugars & Metabolism: Subjects (n=20) have completed 24-h energy expenditure, satiety, & stress protocols in the WHNRC calorimeter as part of the sugar dose response study. Unique Neural-Adipocyte Genes: Tusc5 & SNCG are expressed in fat cells & peripheral neurons that sense temperature, pain, & other signals. It was found that the genes for these factors are targets of molecules that activate a metabolic pathway (PPARg) important to metabolic regulation. Adipose Tissue Inflammation: A new factor, CD11d, was found to have the highest relative increase in expression in the fat tissue of obese vs. lean animals. Dairy food, but not high calcium alone, markedly reduced inflammation in the fat, suggesting bioactives in dairy attenuate inflammation associated with metabolic disease. Intermediary Metabolism of Sugar & Fats: Increased blood levels of certain amino acids & novel molecules in type 2 diabetics were correlated with poor blood sugar control & poor fat combustion, highlighting the close link between dysfunction & metabolism of multiple nutrients in diabetes. Dietary Fats: Techniques were developed to isolate, separate, & quantify lipid metabolites within lipoprotein particles, providing the ability to investigate the functional impact of perturbed lipid metabolism as occurs in obesity & diabetes. Znt7: Male Znt7 knockout (KO) mice fed a high fat diet developed hyperinsulinemia & impaired glucose clearance; Znt7 KO mice fed a low fat diet had reduced glucose clearance, indicating that defects in insulin production/secretion and/or peripheral tissue insulin sensitivity are due to the defect of Znt7. These preliminary data were included in an innovation award application to American Diabetes Association. Pancreatic beta-cells: Over expression of Znt7 in beta-cells increased total cellular insulin levels leading to high basal insulin secretion. Manuscript describing this work has been accepted for publication in Experimental Cell Research. Body weight gain in Znt7 knockout mice: A preliminary QTL mapping study was completed and 8 QTLs were identified that were associated with epididymal fat mass & body weight. Additional SNP markers & animals will be added to increase the power in this QTL mapping study. Accomplishments 01 Middle-aged, perimenopausal obese and normal weight women present a good model for assessing behavioral and physiological mechanisms of stress. Life transition periods, such as perimenopause and middle age, are commonly associated with vulnerability to psychological stress, and wome can gain significant weight in mid-life. The roles of stress or stress hormones and their relationship to food choices and body weight or composition during this transition period are unknown. ARS researchers a Davis, CA established a test paradigm to examine an individual�s vulnerability to the effects of stress on food selection, dietary patter and body weight changes. We discovered that differences cortisol responsiveness to a social stress test predict self-selected palatable food intake from a snack buffet and body fat composition in perimenopaus women. These findings demonstrate that stress reactivity interacts with body fat to influence food choice and food intake. 02 Compared to women, men who consume large quantities of beverages sweeten with fructose, are prone to metabolic dysfunction following ingestion of meals. The use of fructose-containing sweeteners has increased in parall as obesity has become more prevalent in our society. Little is known abo how consumption of large quantities of fructose affect metabolism of sugars and fats in humans. In collaboration with University of Californ Davis scientists, ARS researchers at Davis, CA found that regular consumption of fructose-sweetened beverages over 10 weeks led to a preference for burning sugar to produce energy, but not fat�an effect th was particularly pronounced among men. Further, as the ability to burn fat was reduced, body fat accumulated in the abdominal region. These findings demonstrate, for the first time, that regular consumption of sweeteners containing fructose can cause an accumulation of body fat in individuals that have limited capacity to burn fat for energy. 03 Inflammation in adipose tissue: the roles of specific nutrients and food such as calcium and dairy products, on this phenomenon. ARS researchers at Davis, CA studied mice fed high-fat diets with different sources of calcium. Inclusion of dairy as the primary protein source led to significantly lower body fat, reduced weight gain, more limited inflammation, and improved blood sugar control without lowering food intake. In contrast, mice fed the high fat diet with high calcium and n dairy actually gained more weight, were fatter, and displayed increased inflammation. Dairy foods and calcium are considered components of a healthy diet, and have been implicated in healthy body weight control. has not been clear if the latter is due to mineral calcium or factors specifically associated with dairy foods. This study established that dairy protein factors and/or dairy carbohydrates are key to the positive metabolic effects of dairy foods, which calcium alone cannot mimic. 04 Alterations in intermediary metabolism of sugars and fats in obesity and diabetes. Metabolism of sugars, fats, and proteins are perturbed in obesity and diabetes. ARS scientists at Davis, CA, in collaboration with scientists at the University of Alabama at Birmingham and UC, Davis conducted a comprehensive comparison of small molecules (metabolites) in the blood plasma of non-diabetic vs. type 2 diabetic (T2D) obese African American women. In T2D women there is abnormal metabolism of the buildin blocks of proteins (amino acids; likely due to perturbation in amino aci breakdown), and that a unique metabolite signature tracks blood sugar control. New methods were developed that allowed metabolite profiling in sub cellular structures called mitochondria (sites of nutrient conversio to energy). Disruptions in normal fat metabolism in these structures is believed to underlie some of the poor outcomes of T2D by influencing export of important molecules that support sugar, amino acid, and fat utilization. The newly-identified metabolites that tracked blood sugar markers may have utility as new biomarkers for predicting diabetes risk clinically and could be used to track efficacy of strategies designed to thwart the disease. The new insights from mitochondrial studies enabled formulation of a testable metabolic model in which T2D tissues are believed to have compromised mitochondria in part due to dysfunctional loss and poor replenishment of key metabolites that support normal metabolism. 05 The unique peripheral neuron-adipocyte gene, Tusc5�biological roles are associated with adiposity and gene regulation by nutritional and environmental cues. A gene-regulating protein termed peroxisome proliferator activated receptorgamma (PPARg) is a master controller of f metabolism and fat cell (adipocyte) growth and function. Previous studie conducted by ARS researchers at Davis, CA suggested that the newly- characterized adipocyte factor Tusc5 is regulated by PPARg, raising the possibility that Tusc5 is involved in the physiological changes in metabolism pathways and new fat cell differentiation that is triggered b stimulators of PPARg such as certain lipids or diabetes drugs. Recent studies using mouse cells have now firmly established that regions of th Tusc5 gene physically interact with PPARg, proving it to be a bona fide target gene. However, in diabetic humans treated with PPARg agonist drug fat tissue Tusc5 expression was not stimulated. While not discounting th potential importance of Tusc5 for normal fat tissue function, its lack o apparent involvement in PPARg-related changes in humans indicate that future studies by researchers to explore function in people should focus away from PPARg associations. 06 Obesity is associated with mild inflammatory conditions. A mild inflammation state may be involved in some of the obesity related advers health effects, but our ability to measure mild inflammation is limited. Researchers at ARS, Davis, CA in collaboration with international collaborators in the Netherlands, studied obese men who were treated wit diclofenac, an over-the-counter pain medication, to identify obesity- associated changes in inflammatory mediators and genes. A number of potential markers of chronic inflammation in obese men were identified that may be prognostic of risk of the development of obesity-related chronic disease states, which if translated into clinical practice would enable earlier and more targeted nutritional or pharmacologic interventi to thwart metabolic disease. 07 Does consumption of omega-3 fatty acids have anti-inflammatory effects, reducing pro-inflammatory metabolite levels? More scientific evidence i needed to determine if consumption of omega-3 fatty acids significantly reduces inflammation in humans. ARS Researchers at WHNRC, Davis, CA, fe overweight and obese men fatty acid supplements, and measured levels of pro- and anti-inflammatory lipid metabolites. Individuals with the highest levels of pro-inflammatory metabolites at baseline showed the greatest reduction in these metabolites, while those with the lowest levels of these compounds showed no changes with supplementation. Measurements of these compounds in blood serum can provide an indication of a therapeutic need for omega-3 fatty acid supplements, and, if consum regularly, these supplements will effectively reduce inflammatory metabolites. 08 Biological roles of different sub-classes of polyunsaturated fatty acids The USDA Dietary Guidelines make recommendations on saturated, monounsaturated, and polyunsaturated fatty acids to promote health in th general population. However, sufficient evidence to support recommendations on specific polyunsaturated fatty acids, such as omega-6 (n6) and omega-3 (n3) forms of PUFA does not exist. By altering the relative amounts of these fats in a rodent-based feeding study, ARS researchers at Davis, CA found that regardless of n6/n3 ratios, moderate high fat diets (40% caloric fat) with controlled saturated and mono- unsaturated fatty acid do not produce significant weight gain or changes in clinical lipid chemistry panels when fed to healthy hamsters. Moreov low fat diets (12% caloric fat) showed distinct differences in circulating monounsaturated fatty acids, and dietary lipids produced subtle, but distinct impacts on liver gene expression. The impact of thi result is currently being more fully investigated. 09 Zinc is important in glucose metabolism. Overweight and obesity are maj health concerns in the developed countries as these conditions are associated with a number of serious and costly chronic medical condition including type 2 diabetes, cardiovascular disease, hypertension, osteoarthritis, and certain cancers. Connections between zinc nutrition and homeostasis with metabolic diseases remain largely unknown. Using a zinc transporter (Znt7) knockout mouse model and cell cultures overexpressing Znt7, ARS researchers in Davis, CA discovered that loss o Znt7 leads to poor blood sugar control due to abnormal blood levels of t glucose-regulating hormone insulin, and increased Znt7 in pancreatic bet cells (cells that produce insulin) increased insulin expression and basa insulin secretion. It was demonstrated, for the first time, that the insulin genes (Ins1 and Ins2) in rodents are targets of the metal- responsive transcription factor Mtf1 that is activated by zinc. These studies establish the importance of cellular zinc in regulation of insul synthesis and secretion and thus control of blood sugar level, and highlight that proper zinc nutrition and beta-cell zinc handling could b important for maintenance of metabolic health. 10 Identification of quantitative trait loci (QTLs) that influence body weight gain in Znt7 knockout mice. A direct link between body weight regulation/adiposity and zinc homeostasis is lacking, but ARS researcher in Davis, CA recently discovered that mice lacking the zinc transporter protein Znt7 are leaner even when fed a high fat diet. The mechanisms f this phenomenon may involve factors including oxidative and inflammatory stress, endocrine secretion/signaling, energy partitioning, glucose homeostasis, carbohydrate and lipid metabolism, and adipocyte differentiation/proliferation. Quantitative trait loci (QTLs: chromosomal regions statistically associated with a particular characteristic such as body fat) are a valuable resource to identify candidate genes responsible for the lean characteristics of Znt7 knockou mice, and a QTL mapping approach in the knockout mice revealed QTLs associated with body weight as well as fat pad weight on chromosomes 10, 16, and 19. This study is the first to identify genetic regions that associate zinc metabolism to body weight and adiposity (body fatness), i support of a role for proper zinc nutrition and cellular zinc handling i maintaining body weight and metabolic health, and provides a set of candidate genes that will form the basis for future experiments to identify those most prominently involved in the zinc-body weight association.

Impacts
(N/A)

Publications

  • Campbell, J.C., Laugero, K.D., Van Westerhuyzen, J.A., Hostetler, C.M., Cohen, J.D., Bales, K.L. 2009. Energetic costs of pair bonding and parental care in male prairie voles (Microtus ochrogaster). Physiology and Behavior. 98:367-373.
  • Knotts, T.A., Lee, H., Kim, J., Oort, P.J., Mcpherson, R., Dent, R., Tachibana, K., Doi, T., Yu, S., Reddy, J.K., Uno, K., Katagiri, H., Pasarica, M., Smith, S.R., Sears, D.S., Grino, M., Adams, S.H. 2009. Molecular Characterization of the Tumor Suppressor Candidate 5 Gene: Regulation by PPARg and Identification of TUSC5 Coding Variants in Lean and Obese Humans. Trade Journal Publication. PPAR Research Vol. Article ID 867678. 1-13, 2009.
  • Laugero, K.D., Stonehouse, A.H., Guss, S., Landry, C.V., Parkes, D.G. 2009. EXENATIDE IMPROVES HYPERTENSION IN A RAT MODEL OF THE METABOLIC SYNDROME. Metabolic Syndrome and Disorders. 7(4):327-34, 2009.
  • Townsend, M., Grant, A., Monsivais, P., Keim, N.L., Drewnowski, A. 2009. Lower-energy-density diets of low-income women in California are associated with higher energy-adjusted diet costs. American Journal of Clinical Nutrition. 89:1220-1226, 2009.
  • Gurusinghe, D., Gill, S., Almario, R.U., Lee, J., Horn, W.F., Keim, N.L., Kim, K., Kasim-Karakas, S.E. 2009. In polycystic ovary syndrome, adrenal steroids are regulated differently in the morning versus in response to nutrient intake. Fertility and Sterility, 93(4):1192-1193, 2009.
  • Seifert, E.L., Fiehn, O., Bezaire, V., Bickel, D.B., Wohlgemuth, G., Adams, S.H., Harper, M. 2010. Long-chain fatty acid combustion rate is associated with unique metabolite profiles in skeletal muscle mitochondria. PLoS One. Volume 5(3) pp. 1-13, 2010.
  • Shearer, G., Newman, J.W. 2009. Impact of circulating esterified eicosanoids and other oxylipins on endothelial function. Current Atherosclerosis Reports. Vol. 11:403-410.
  • Van Erk, M.J., Wopereis, S., Rubingh, C., Van Vliet, T., Verheij, E., Cnubben, N., Pedersen, T.L., Newman, J.W., Age, S., Van Der Greef, J., Hendriks, H., Van Ommen, B. 2010. Insight in modulation of inflammation in response to diclofenac intervention: a human intervention study. Biomed Central (BMC) Genomics. 3:5.


Progress 10/01/08 to 09/30/09

Outputs
Progress Report 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. 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) Significant Activities that Support Special Target Populations �5306-51530-019-00D� is a newly-approved project. Progress to date includes establishment of the Project Team and planning for implementation of Objective experiments. A more comprehensive Progress Report will be available at the end of the first year of the new Project(in the FY2010 report cycle).

Impacts
(N/A)

Publications