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.
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.