Location: Obesity and Metabolism Research2011 Annual Report
1a. Objectives (from AD-416)
Objective 1: Evaluate mediators of behavior change critical for adopting a healthy diet by investigating interrelationships between psychosocial stress, nutritional behavior and metabolism in humans and animal models. Objective 2: Determine how diet patterns, whole foods, and food components influence physiology and metabolic health by impacting eating- and neuro-behaviors, energy balance and substrate utilization, fitness, body weight and body composition in humans. Objective 3: Determine mechanisms underlying the regulation of body weight and disorders associated with obesity, by examining hormonal, neuronal, and metabolite pathways linking adipose and non-adipose tissues, and characterizing tissue-specific inflammation in humans, cells, and animal models. Objective 4: Determine the impact of dietary lipids on body weight, adiposity, and/or metabolic health indices by assessing their influence on lipoprotein-dependent trafficking of bioactive lipids to adipose and peripheral tissues, their effects on the regulation of metabolic homeostasis, and their interactions with distinct fatty acid desaturase/elongase activity phenotypes. Objective 5: Characterize the roles of cellular zinc in regulation of lipid metabolism, body fat mass, and fat distribution during postnatal development in genetically-modified animal models. Objective 6. Develop and validate phenotyping tools that classify and predict metabolic and body weight responses to dietary and physical activity interventions in individuals and populations.
1b. Approach (from AD-416)
We will use a multidisciplinary approach to test molecular, physiological, and metabolic responses to diets composed of whole foods or enriched with select macro- and micronutrients, determine how physical activity, stress, and genetic factors modify metabolism and responses to foods, identify important behavioral and psychosocial factors related to adopting the U.S. Dietary Guidelines, and determine basic physiological mechanisms underlying links between nutrition, physical activity, and metabolic health. Our work will use classical investigations of metabolism and energetics, along with metabolomic analyses, real-time determinations of brain activity in response to foods, and gene/protein expression determinations to investigate these questions, linking findings from these approaches to whole-organism phenotypes and human behavioral traits. Randomized controlled trials and analyses of samples from longitudinal observational studies will also be conducted. Important studies in animal and cell culture models will complement this work to gain a deeper understanding of underlying mechanisms and/or to obtain proof-of-concept information before designing and conducting human trials.
3. Progress Report
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.
1. 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. We discovered that person-to-person differences in weight loss were inversely 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.
2. Compositional changes of specific lipid fatty acids may form new functional markers of chronic psychological stress. Psychological stress and the neuroendocrine reaction to stress are associated with mental and physical diseases, such as obesity and depression. However, the response to psychological stress varies from person to person, and this inter-individual variation in the stress response may contribute to differences in disease vulnerability. The physiological basis for differences in stress reactivity and disease remains unknown. Through the application of 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 other specific fatty acid metabolites. Our results support the notion that the association between a dysfunctional stress response and stress related diseases such as depression may be functionally linked by shifts in or pre-existing abnormalities in fatty acid metabolism.
3. 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 increase fat accumulation around the internal organs and within the liver. In 2003 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 produce a definitive change in either abdominal fat or liver fat deposition. These findings support limiting consumption of hydrogenated vegetable oils to reduce cardiovascular risk. However, we found that exposure to high trans fat levels for 16 weeks appears to have only mild effects on the accumulation of body fat in clinically healthy individuals.
4. 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 of 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 technological platforms. This study produced a complete set of 4229 confirmed and highly probable soluble constituents in human blood, their concentrations, 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.
5. Vitamin B12 status is an important factor in the assessment of health in the old and very young. Serum concentrations of methylmalonic acid are a broadly used biomarker of vitamin B12 status. We have carefully optimized 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 µL. The reported method is especially useful for studies of functional B12 status in sample-limited experiments including investigations of nutritional status in newborns, making some such studies possible for the first time.
6. 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 nutritious 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 results 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, such an approach has potential to yield significant health care cost savings.
7. 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 metabolism (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 improve health. Initial evidence suggests that dietary protein quality may elicit tissue-level changes in lipid transport that promote metabolic efficiency, and thus such dietary change holds promise to reduce metabolic complications or development of diabetes.
8. Dietary lipids impact circulating bioactive metabolites. The ingestion of 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 weakly 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 circulation which may be involved in the beneficial effects of diets rich in these materials.
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.