Location: Obesity and Metabolism Research2015 Annual Report
Objective 1: Compare metabolic, physiologic, and behavioral responses to consumption of a high quality vs. typical American diet pattern. Sub-objective 1A. Determine if a diverse, DGA-based nutrient-rich diet elicits a superior metabolic profile in persons at-risk for metabolic disease, compared to the typical U.S. diet that strays from the DGA with respect to saturated fats, added sugars, fiber, and dairy servings. Sub-objective 1B. Determine if chronic stress, stress system responsiveness, and diet quality interact to influence metabolic health. Sub-objective 1C. Determine the effect of diet quality and physical activity level on the plasma metabolomic response to a mixed macronutrient challenge. Sub-objective 1D. Determine if combining assessment of dietary intake using the 24-h recalls, physical activity assessments, anthropomorphic measures and fasting biomarkers of hepatic lipogenesis will improve prediction of insulin sensitivity assessments over the use of fasting glucose and insulin. Objective 2: Discover interrelationships between metabolically important tissues that contribute to metabolic health and energy homeostasis. Sub-objective 2A. Characterize the gut (fecal) microbial populations in response to dietary interventions based on the Dietary Guidelines or the typical American diet, and determine how they are related to metabolic outcomes. Determine the contribution of gut microbiota to the systemic metabolome. Sub-objective 2B. Characterize metabolic phenotypes and alterations in physiological network cross-talk that correspond to unhealthy and healthy overweight/obesity states. Sub-objective 2C. Investigate the causes of inflammation and cellular stress responses that are associated with obesity, insulin resistance and metabolic syndrome: the roles of specific metabolites and perturbations in metabolic pathways. Objective 3: Identify physiological and psychological processes that influence behavior related to food intake. Sub-objective 3A. Link individual differences in eating behavior with metabolomics and endocrinology of hunger and satiety. Sub-objective 3B. Vulnerability and resilience to stress may be determined by metabolic responses to stress: implications for stress-eating.
We will use a multidisciplinary approach to test molecular, physiologic, and metabolic responses to diet patterns, specific nutrients, and physical activity levels to determine effects on or associations with chronic disease risks. We posit that consumption of a diet, patterned on the Dietary Guidelines for Americans (DGA), will rapidly improve cardiometabolic risk factors, improve gut barrier function and reduce metabolic dysfunction. Also, individual differences in chronic stress and stress system responsiveness will partially explain variation in metabolic responses to the DGA diet. A randomized, food-controlled trial will be conducted to test these hypotheses. We will also conduct a cross-sectional study using metabolomics to map an individual’s metabolic flexibility and link this phenotypic trait to lifestyle, including markers of health status, physical activity parameters, diet quality, food preferences and food choices. As part of this study, we will administer a meal challenge to test the hypothesis that behavioral phenotypes can be identified based on responses of known and putative satiety signals to the meal. Using the cross-sectional approach and metabolomic analyses, we will develop basal and stress-induced metabolite profiles to identify differential stress-response signatures. Ancillary studies will be conducted to examine underlying mechanisms that might explain metabolic dysfunction. To examine gut microbiota and metabolites in more depth, samples of adipose, liver, intestinal content, and blood from ‘healthy’ and ‘unhealthy’ obese undergoing gastric bypass surgery will be used to derive phenotypic signatures spanning several biological systems and adipose tissue structure/function to test the hypothesis that phenotypic signatures can predict improvement in insulin resistance and inflammation. Using a murine model of diet-induced obesity, we will test the hypothesis that obesity disrupts the normal association between peripheral nervous system (PNS) sensing of ambient temperature and communication to the brain to coordinate temperature-control of feeding and energy expenditure. This study will include functional tests in vivo, and PNS expression of temperature-sensing TRP channels will be evaluated in dorsal root ganglion ex vivo. Finally, cultured muscle cells will be used to examine the hypothesis that incomplete mitochondrial combustion of fatty acids in tissue such as muscle leads to increased acylcarnitine accumulation, and select acylcarnitines promote cell stress responses will be evaluated.
Progress was made on all three objectives, all of which fall under National Program 107, Component 3: Scientific Basis for Dietary Guidance and Component 4: Prevention of Obesity and Obesity-Related Diseases. Progress on this project focuses on the conduct of two important human trials that were designed to address the variability in human metabolism as it relates to dietary intervention or to habitual dietary intake. Essential steps were taken to implement a randomized controlled trial to examine the health benefits of a diet pattern based on the Dietary Guidelines for Americans. The study was approved by the Institutional Review Board and nearly 100 potential participants have been screened for eligibility. The target sample is females at risk for metabolic disease; in this first year, 12 participants have enrolled with the goal of enrolling 60 participants over the 4-year project. The intervention study serves as the foundation for sub-objectives 1a, 1b, and 2a. Partial support for this study is coming from subordinate project 2032-51530-002-20T with Dairy Research Institute, entitled, "Evaluation of Health Benefits of a High-quality Diet in Persons At-risk for Development of Metabolic Disease: Rapidity & Weight-independent Effects." Protocols were developed to characterize nutritional phenotypes in individuals through the application of a series of metabolic, physical and neuropsychological challenge tests. Pilot studies were conducted to establish the utility of the proposed metabolic endpoints. A state-of-the-art liquid chromatography/tandem mass spectrometry system was purchased and installed at the Western Human Nutrition Research Center (WHNRC), and method developments have been initiated to streamline and thus reduce projected costs of the project. We also developed and reported a novel statistical approach to identify differences in metabolic phenotypes within populations, based on biochemical product/substrate relationships in the plasma. A protocol for fecal sample collection, homogenization and storage was developed that will enable characterization of the fecal microbiome as well as targeted excreted metabolites. These procedures support the dietary intervention study as well as a cross-sectional phenotyping study. The phenotyping study was approved by the Institutional Review Board and commenced in June 2015 with approximately 30 subjects enrolled out of a total of 400 participants needed over the course of the 4-year project. The phenotyping study serves as the foundation for sub-objectives 1c, 1d, and 3a in this project plan. Sub-objective 3b was addressed with a metabolomics investigation of archived samples to evaluate the interaction between stress responsivity, chronic stress, and the metabolic response to an acute stress, and reports of this work have been presented at an international conference and submitted for publication. For agreement 58-5306-037F, with the University of Copenhagen, Denmark, titled “The Role of Cyclooxygenase in Responses to High Fat Diets”, oxylipin profiles were quantified in C57B6 and AJ129 mice on high fat diets with variable durations of cold stress. Preliminary analysis indicates that the cold sensitive AJ129 animals have a dramatic upregulation of adipocyte cyclooxygenase activity. Results have been transmitted to the collaborator, and manuscript preparation is in progress. In a secondary study, humans with high and low levels of intrascapular brown fat were identified and mediator profiling and untargeted metabolomics analyses were performed on brown and white fat biopsies. Biostatistical analyses were performed showing discrete metabolic patterns in both brown vs. white adipose, and between similar tissues from subjects with either low or high brown fat phenotypes. Understanding how complex diets affect lipid mediator profiles in adipose and plasma, and identifying factors leading to variability in such responses, are fundamental questions within the parent project which are enriched by this subordinate project. For agreements 58-5306-4-043F and 58-5306-4-050F, with the Capetan Vasillis Foundation and GAEA Products S.A. respectively, which are 50/50 co-funders of a pilot project titled “Impact of Extra Virgin Olive Oil Oleocanthal Content on Platelet Reactivity in Healthy Humans” extra virgin olive oils (EVOO) from different olive cultivars were identified by their oleocanthal, oleacien, and total phenolic concentrations. Four oils were selected with either a high oleocanthal:oleacein ratio, a low oleocanthal:oleocien, or with low oleocanthal and oleacin, but equivalent total phenolics. Subjects have been recruited and 5 of 10 have completed the 4 week protocol. A preliminary blinded analysis suggests a diminishing of platelet reactivity in 1 of the test oils, while the hypothesized impact on cyclooxygenase metabolism if substantiated is minimal. Alternative hypothetical mechanisms of the observed effects are being formulated and a broader evaluation of the impact of EVOO variety on metabolism is being planned. Understanding dietary factors which influence adipose function and physiological changes associated with obesity (e.g. inflammation) are related to objective 2 of the parent project. Agreement 58-5306-4-044F, with Bisperbjerg Hospital, University Copenhagen Denmark, titled “Obese Women with Ischemic Heart Disease and Metabolic Syndrome Undergoing Dietary Intervention and Physical Training." Oxylipins were analyzed in plasma samples (n=191) of obese women participating in a diet and exercise intervention study; results were returned to collaborators for statistical analysis within the context of the complete study design. Manuscript preparation is in progress. The assessment of weight loss strategy efficacy in the obese is directly related to objective 2. Understanding how caloric restriction and exercise combine to effect inflammatory mediator profiles in plasma will provide novel insights into the metabolic consequences of these intervention strategies. In agreement 58-5306-4-0013F, with the Saw Swee Hock School of Public Health, National University of Singapore titled “Intercalibration of Oxylipin Analysis for Chinese Heart Study”, method transfer, consultation, and analytical comparisons were completed in 2014. Complete implementation and application of techniques were completed in 2015 and a first draft manuscript has been prepared. This project is aligned with the parent project, addressing a fundamental hypothesis that nutritionally responsive diseases will be reflected in changes in the circulating concentrations of oxygenated fatty acids in the blood. The greater project seeks to evaluate such changes in association with cardiovascular disease risk. The WHNRC is transferring technical expertise to the University of Singapore that they may independently investigate this hypothesis. For log # 0047113, with University of California Davis, the Lipid Mediators Advancement Core was formed as a subcomponent of the West Coast Central Comprehensive Metabolomics Research Center (WCMC), and is housed at the Western Human Nutrition Research Center (WHNRC). In this capacity, the laboratory has developed and implemented quantitative profiling of bile acids and transferred these tools to the WCMC. In collaboration with WCMC staff, a novel 96-well plate sample preparation method has been implemented, greatly reducing labor and instrument costs associated with lipid mediator analyses. As a collaborative partner, the USDA has supported: 1) an investigation of the impact of weight gain/loss on metabolomics profiles of plasma and peripheral tissues; 2) an investigation of insulin and glucagon like peptide-1 infusions on the plasma metabolomics and lipid mediator profiles in a unique animal model of insulin resistance, the fasting Northern Elephant seal; 3) an investigation of the metabolic interaction between ovarian cancer cells and primary adipocytes; 4) an investigation of pre-term infant pulmonary hypertension using a novel nutritional model of the disease; 5) an investigation of the impact of Acyl-CoA Synthetase Long-Chain Family Member 4 (ACSL4) knockout on oxylipin metabolism of the adipose tissue; and 6) an investigation of the impact of milk peptides on sebocyte generation of lipids and lipid mediators of inflammation. Each of these projects is at various stages of manuscript preparation and most have been or soon will be presented at international meetings. The methods developed are fundamental advancements which will facilitate the phenotyping goals (Objective 1) within the current parent project. Results from the collaborative projects will enhance and inform interpretation of phenotypic changes within a nutritional context (Objective 1) and support the discovery of relationships between metabolically active tissues (Objective 2).
1. Sugar suppresses the brain’s stress response in humans. Studies in animal models have suggested that sugar consumption can dampen stress responsiveness, but no systematic investigation in humans has been conducted. ARS scientists in Davis, California, led a ground breaking study using brain imaging technology to test for sugar-dampening effects on stress reactivity and determine if a metabolic-brain stress pathway could be confirmed in humans. Results showed that consumption of large amounts of sugar, but not artificial sweetener, provided stress relief by suppressing neural circuits in the brain and the release of the stress response hormone, cortisol. These findings provide evidence as to why sugar may positively reinforce its habitual consumption in people experiencing persistent stress. Confirmation that sugar, indeed, is stress-modulating in humans presents the possibility for new therapies to alter stress-associated diseases of the brain such as depression and anxiety.
2. Chronic mental or emotional stress may predispose individuals to obesity. Exposure to stress may alter brain pathways in ways that lead to stronger reactions to highly rewarding (typically high in calories) foods. ARS researchers at Davis, California, in collaboration with University of California-Davis Medical Center researchers, conducted a neuroimaging (fMRI: functional magnetic resonance imaging) study to examine how chronic stress affects activity in the brain when viewing pictures of high calorie foods. The study showed that women reporting higher chronic stress and viewing pictures of high calorie foods had exaggerated activity in brain regions linked to reward and emotional-based food intake, and reduced activity in regions that mediate self-control and decision making. In a parallel study of these women, higher chronic stress was associated with eating more high-fat/sweet foods from a voluntary snack food buffet. This neurophysiological and behavioral evidence supports a biological basis for poor food choice, dysfunctional eating habits, and obesity risk in persons currently or previously experiencing chronic stress.
3. Bioactive lipids in circulating lipoproteins. The human body produces compounds that mediate inflammation and vascular function when and where they are needed, but it is not known how this is accomplished. To investigate the possibility that lipoproteins circulating in the blood might be a shuttle system for specific mediators, a study was conducted with humans taking lipid-lowering medications and given dietary treatment with omega-3 acid ethyl esters, compounds known to influence inflammation and vascular function. ARS researchers at Davis, California, with collaborators at the Pennsylvania State University, found that the omega-3 ester preparation decreased pro-inflammation mediators across all lipoproteins, and greatly expanded anti-inflammation mediators. Each different lipoprotein fraction carried a unique complement of these bioactive lipid metabolites and overall dietary omega-3 fatty acids altered the lipoproteins in a manner consistent with vascular health benefits. These findings contribute to our understanding of how certain dietary lipids are metabolized and transported to tissues to exert important pro- or anti-inflammatory effects.
4. Improving health-promoting properties of farmed salmon. Introduction of vegetable oil ingredients into fish feed affects the fatty acid composition of farmed salmon, which may alter the healthfulness of this commodity. ARS scientists at Davis, California, and collaborators in Norway, investigated if the type of oil used to prepare fish feed affected the metabolism of mice fed diets containing farmed salmon fillets. When the oil in the fish feed was switched from fish oil, high in omega-3 fatty acids, to soybean oil, high in omega-6 fatty acids, pro-inflammatory mediators increased in the livers of mice eating salmon raised on feed rich in omega-6 oils. This alteration of liver mediators was associated with increased insulin resistance and accumulation of liver fat. These findings underpin the need for carefully considering the type of oil used for feed in salmon farming, and indicate that the use of omega-3 rich vegetable oils such as rapeseed oil may yield a healthier salmon product.
5. Human variability in response to caloric restriction. Weight loss caused by reducing energy intake is highly variable among individuals even under tightly-controlled conditions. Knowledge of factors that could predict a person’s ability to respond to caloric restriction would be a valuable weight management tool in the clinic, and provide insight into the fundamental biology regulating body weight. ARS scientists at Davis, California, conducted a comprehensive analysis of data collected on overweight people enrolled in a weight loss regimen with all food controlled, searching for variables that were related to changes in body weight. Of more than 900 variables considered, measures of physical activity level, sedentary behavior, and ability to use fat as an energy source were associated with the amount of weight loss. Results suggested that as a persons’ level of sedentary behavior increased, their ability to increase use of stored fat to meet their energy demand was decreased. While this study provides strong evidence for why some individuals do not experience weight loss with caloric restriction, the findings were not powerful enough to predict who would and would not lose weight using baseline data alone.
6. A new approach for comparing metabolic variation in populations. Datasets containing information about an individual’s metabolism and inherited DNA modifications are valuable for analyzing disease risk, but new approaches are needed to improve their use. ARS scientists at Davis, California, validated a “mixing” model using biomarkers of fatty acid metabolism derived from a study of acute coronary syndrome (ACS). Rather than assuming that a population is best described by a single average behavior, mixing models assume that discrete populations may exist, and characterizing these discrete populations can be useful to identify groups of people who have different metabolic capacity. The mixing model approach identified discrete metabolic sub-populations that decreased or increased the odds for the development of ACS, thereby improving the power and sensitivity of risk detection compared to classic statistical approaches. This novel model can be applied in studies that examine the link between dietary intake, metabolism, and health status potentially impacting future dietary recommendation strategies.
7. The endocannabinoid system responds to dietary fatty acids. The endocannabinoid system (ECS) is a neurometabolic system that is thought to play a role in energy balance and immune function, and its over-activation is associated with increased adiposity. Little is known about nutritional effectors of the ECS system. Using male mice, ARS scientists in Davis, California, and their collaborators, investigated whether dietary docosahexaenoic acid (DHA), a long-chain omega-3 fatty acid, could reduce ECS over-activation and thereby influence control of blood glucose. The DHA-rich diet diminished ECS activation and provided numerous metabolic benefits including enhanced muscle glucose metabolism, reduced body fat, and reduced systemic inflammation. This study provided a clear demonstration that a specific nutritional intervention can indeed impact the ECS.
8. Walnut consumption and vascular function. Although walnuts have been shown to improve vascular function, the mechanisms underlying this effect are poorly defined. ARS scientists at Davis, California, in collaboration with colleagues at the Pennsylvania State University and the University of California-Davis, conducted a study with postmenopausal women to investigate if changes in vascular function associated with walnut intake were related to changes in lipoprotein and plasma fatty acids and lipid mediators of vascular tone. They discovered that the vasculature’s ability to respond to a stressor of low oxygen levels was related to the levels and types of lipid metabolites in the high density lipoproteins circulating in blood. These results demonstrate that the consumption of walnuts can improve microvascular function, and the extent of this improvement is associated with specific changes in fatty acids and lipid metabolites. These data confirm that intake of walnut-derived fatty acids can favorably influence microvascular function and increase our understanding of how these fatty acids exert such effects.
9. Cortisol and blood pressure in breakfast skippers. Observational studies suggest that omitting the breakfast meal on a regular basis may be detrimental to health, but a physiological basis that would connect regular breakfast skipping and poor health in humans remains undetermined. In a study of regular breakfast eaters and breakfast skippers, ARS scientists at Davis, California, examined risk factors of cardiovascular and metabolic disease to determine if these risk factors were associated with salivary cortisol, a stress hormone linked to poor blood glucose control, obesity, and high blood pressure. Results showed that women who regularly skipped breakfast had evidence of elevated cortisol levels, a disrupted daily cortisol rhythm, and higher blood pressure. These results provide the first evidence in humans demonstrating that habitual breakfast skipping may disrupt cortisol rhythms, which may explain higher blood pressure and other previously described cardiometabolic dysfunction in persons habitually skipping breakfast.
10. Beverages sweetened with high fructose corn syrup (HFCS) and cardiovascular disease risk. There is controversy regarding the consumption of simple sugars and the potential to increase risk of chronic disease. To date, many of the controlled experiments conducted in humans have incorporated very high levels of sugars in the diet. Working with University of California-Davis investigators, ARS scientists in Davis, California, tested the effect of drinking beverages sweetened with HFCS, providing high, moderate, low, or no calories from this sweetener in the daily diet of young adults. The research team found that even with the low sweetener dose, common risk factors for heart disease increased, and this risk grew larger as the amount of sweetener in the diet increased. These findings suggest that regular consumption of the sweetener HFCS in beverages, even at low doses, may contribute to greater risk of heart disease, and more research is needed to determine prudent levels of this form of added sugar in the diet.
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