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ARS Home » Pacific West Area » Davis, California » Western Human Nutrition Research Center » Obesity and Metabolism Research » Research » Research Project #426826

Research Project: Improving Public Health by Understanding Diversity in Diet, Body, and Brain Interactions

Location: Obesity and Metabolism Research

2018 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. New Sub-objectives 2B and 2C as of 1-31-2017 to reflect change in personnel expertise: Sub-objective 2B. - Identify and validate pathways that regulate plasma TMAO levels and susceptibility to cardiometabolic disease. Sub-objective 2C- Identify resident Gut Microbial Taxa that regulate plasma TMAO levels and atherosclerosis susceptibility. 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 Report
Progress was made on all three objectives, with research focused on the conduct of two important human trials designed to address the variability in human metabolism as it relates to dietary intervention or to habitual dietary intake and complementary animal model studies. For Sub-objectives 1A and 1B, clinical and physiological data collected for the study that examined the health benefits of a diet pattern based on the Dietary Guidelines for Americans (DGA) were analyzed. The first peer-reviewed manuscript, published August 2018, reported decreased systolic blood pressure after eating the DGA diet for two weeks, but no effect of the DGA intervention on glucose tolerance was found. Outreach activities were done to familiarize professionals and consumers about this study at the California Academy of Nutrition and Dietetics and the California Area Indian Health Service. Additional analyses related to the response to a lipid challenge and overall gut health are in progress. Psychological stress and cognitive function were measured in the DGA study, and preliminary analysis indicates that reaction time improved in response to the DGA diet. Increases in reaction time suggest improvements in general neurological processing, overall motor capability, and/or the health status of neurological mechanisms that link one’s perception of an external stimulus and the ability to behaviorally respond. In a parallel examination, and compared to a more typical American diet (TAD), self-reported feelings of stress were lower after exposure to the DGA diet, but this was only observed in subjects whose intake of omega-3 fatty acids increased compared to their usual pre-study intake. Given that omega-3 fatty acid status in the body and dietary omega-3 have been linked to how the brain emotionally responds to stressful conditions, these findings suggest that the DGA diet, which was higher in omega-3s relative to the TAD diet, reduced feelings of stress, particularly in those who typically consume low amounts of omega-3 fatty acids. For Sub-objective 2A, a characterization of the fecal microbiota, comparing the response to the DGA and TAD, is proceeding with colleagues at the ARS Arkansas Children’s Nutrition Center, Little Rock, Arkansas. These results will be paired with a wide variety of metabolomics analyses including target assays for classic lipid metabolism and dietary lipids that are complete, and broader metabolomics profiling that is approximately 25% complete. For Sub-objectives 1C, 1D, and 3A, subjects continue to be enrolled in a cross-sectional phenotyping study, and a total of 275 subjects have fully participated (396 are needed over the course of the project). Analyses of metabolic regulators of energy metabolism, inflammatory mediators, plasma lipids, and red blood cell fatty acids (a marker of habitual diet lipids intake) have been completed for the first 120 subjects. Preliminary analysis of plasma esterified and non-esterified fatty acid responses to a mixed macronutrient challenge test from the first 50 subjects identified five distinct response patterns. Habitual dietary intake was associated with one of these distinct response patterns. In partial fulfillment of Sub-objective 2B, which aims to identify and validate pathways that regulate plasma Trimethylamine N-oxide (TMAO) levels and susceptibility to cardiometabolic disease, ARS researchers have completed measurements on the in-house DGA intervention study and the first 200 participants of the cross-sectional study. Additionally, collaborative studies have identified hepatic expression of mir-146, and genes Numb and Dlst form a genetic pathway that influences plasma TMAO levels. A manuscript is under review describing these results, and results have been presented at a Keystone Conference and a Federation of American Societies for Experimental Biology Conference. To identify resident gut microbial taxa that regulate plasma TMAO levels and atherosclerosis susceptibility (Sub-objective 2C), samples are being collected from mice and will be analyzed during the next fiscal year. Under a collaboration with the West Coast Metabolomics Center at University of California, Davis, ARS scientists are responsible for supporting collaborative research in nutritionally relevant metabolomics. The project provides an opportunity for greater stakeholder engagement and method advancement relevant to the goals of Objectives 1 and 3. The agreement involves analytical resource sharing and consultation with senior personnel in the design and implementation and analysis of research projects, attending monthly seminars, bi-annual strategic planning meetings, and ad hoc consultation on personnel selection and strategic planning of the West Coast Metabolomics Center. In 2018, collaborative efforts focused on: 1) fiber and gut health research (validation of a short chain fatty acid/bile acid fecal analysis); 2) inflammation and clinical phenotyping - a) expansion of lipid mediator and anti-inflammatory medicine analysis, b) plasma bile acid/steroid hormone fusion, c) optimized high-throughput vitamin B12 status assay; 3) impacts of diets and dietary components on health and metabolism; and 4) exploring biochemical alteration associated with diet-sensitive diseases. All methods developed in this reporting year were fundamental advancements that will support the phenotyping objectives crucial for Objectives 1, 2 and 3. For agreement 58-2032-8-001FN with the National Institute of Agricultural Research (INRA), France, ARS scientists at Davis are collaborating in an international round-robin exercise in the quantitative analysis of esterified oxylipins as biomarkers of adverse cardiovascular health outcomes. These methods for the analysis of esterified oxylipins are being used in support of Objective 1, allowing the direct comparison of the ARS data with that of the European effort. After an initial meeting in Paris, France, where progress on Objective 1 was presented, ARS scientists participated in quarterly video conferences, providing expert opinions on study design, implementation, and cohort selection. A novel set of high value analytical standards has been provided to ARS and other collaborators to execute this work. The work is expected to be completed by October 2018. For agreement 2032-51530-022-44I with the National Institute of Health, mice expressing the genes ApoE3*Leiden and cholesteryl ester transfer protein (CETP) are being bred with 100 Diversity Outbred mice. The offspring of this cross have been fed a high fat, high cholesterol diet for 12 weeks and samples were collected. ARS researchers will begin phenotyping these mice for TMAO levels and microbiota composition beginning in October 2018. These data will be related to atherosclerotic lesion size and plasma lipid levels. It is anticipated that all lab analysis of the current mice will be completed by March 2019. Confirmatory studies will be performed over the next year. For agreement 2032-51530-022-39R, with Sonomaceuticals LLC, a randomized controlled study in humans using Chardonnay grape pomace powders is underway to determine if the pomace preparations have important effects on gut health or cardiovascular risk. Enrollment of research volunteers is approximately 75% complete, and in-house laboratory analyses are in progress. For agreement 2032-51530-022-56S, with Arla Foods, the Western Human Nutrition Research Center (WHNRC) cross-sectional phenotyping study (Sub-objectives 1C, 1D, and 3A) serves as the foundation for this agreement. Participants who are either high or low consumers of dairy products are being selected for an exploratory study of the effects of dairy intake on satiety. To date, 25 dairy consumers and 35 non-consumers have been identified. All physiological phenotyping is complete for the subjects selected; 15 dairy consumers and five non-consumers are still needed to complete the dataset. Analyses of parameters that are related to satiety have begun in FY2018, and completion is expected in FY2019.

1. Obesity-induced metabolic changes persist after weight loss. About 45 million Americans attempt to lose weight annually, but sustained reduced body weight is rarely achieved. Scientists at the University of California, San Diego, and ARS scientists in Davis, California, conducted a study to determine if obesity induced metabolic changes persist after weight loss in mice. Although most metabolic dysfunction associated with obesity was reversible with weight loss, adipose tissue retained a persistent obese metabolic signature, manifest as elevated hematopoietic prostaglandin D synthase (HPGDS) and its metabolic products. Increased HPGDS expression was also observed in obese human adipose tissues, and circulating levels of prostaglandin D2, a positive regulator of appetite, were not only elevated in obese patients relative to lean subjects, but did not decrease after significant weight loss. HPGDS may be a critical focal point associated with weight regain that warrants further study.

2. Infant cortisol stress-response is associated with thymic function and vaccine response. ARS and University of California, Davis, researchers in Davis, California, studied a possible physiological mechanism explaining person-to-person variation in effectiveness of vaccination-induced immunity. Researchers found acute reactions of the stress hormone, cortisol, to vaccination were associated with immune system function of Bangladeshi infants participating in a randomized, controlled trial. In boys, higher cortisol reactions associated with lower thymus size, indicating lower immune function. Higher vaccine-induced cortisol reactions in both sexes were associated with reduced concentrations of key immune cells, naïve helper T-cells, and with dampened cell-mediated immunity in both sexes. These results indicate that cortisol reactions during vaccination may mark or determine specific aspects of vaccine-related immune function that mediate long-term immunity and protection from certain diseases in these children.

3. Evaluating a computer-led dietary assessment method in overweight and obese women during weight loss. Accurate dietary assessment is crucial to effective weight loss, and new technologies for dietary assessment are needed. ARS and University of California, Davis, researchers in Davis, California, demonstrated support for a computer-led dietary assessment tool, Automated Self-Administered 24-hour recall (ASA24), as a valid dietary assessment tool in overweight/obese women participating in a weight loss program. The automated features of ASA24 eliminate the need for clinicians to be trained to administer or to analyze dietary intake. Results from this work support the use of a method that may facilitate improved success in clinician-supervised weight loss programs.

4. Health benefits of consuming whole grain products. Current Dietary Guidelines for Americans recommend consuming more whole grains, but despite this long-standing advice, Americans still consume less than one serving per day of whole grains. ARS scientists in Davis, California conducted a study to determine if providing wheat, corn, and rice in their whole grain forms to consumers would increase whole grain intake and favorably change health-related parameters. After six weeks, whole grains intake was about three to four servings per day, and significant decreases in total cholesterol, low-density lipoprotein (LDL)-cholesterol, and non-High-density lipoprotein (HDL) cholesterol were seen along with increased frequency of bowel movements. These changes were not observed in the control group that was not given whole grains. Thus, increased consumption of whole grains occurred when products were readily available and resulted in improvements in blood lipid levels associated with cardiovascular risk factors.

Review Publications
Liyang, Z., Cozzo, A.J., Johnson, A.R., Christensen, T., Freemerman, A.J., Bear, J.E., Rotty, J.D., Bennett, B.J., Makowski, L. 2017. Lack of myeloid Fatp1 increases atherosclerotic lesion size in Ldlr-/- mice. Atherosclerosis. 266:182-189.
Laugero, K.D., Adkins, Y.C., Kelley, D.S., Mackey, B.E. 2017. Emotion-Based cognition in mice is differentially influenced by dose and chemical form of dietary docosahexaenoic acid. Nutrients. 9(9):993.
Kelley, D.S., Adkins, Y.C., Laugero, K.D. 2018. A review of the health benefits of cherries. Nutrients. 10(3):368. https://doi:10.3390/nu10030368.
Pedersen, T.L., Newman, J.W. 2018. Establishing and performing targeted multi-residue analysis for lipid mediators and fatty acids in small clinical plasma samples. In: Giera, M, editor. Clinical Metabolomics. Methods in Molecular Biology. Volume 1730. New York, NY: Humana Press. p. 175-212.
Tian, J., Zhu, J., Yi, Y., Li, C., Zhang, Y., Zhao, Y., Pan, C., Xiang, S., Li, X., Li, J., Newman, J.W., Feng, X., Liu, J., Han, J., Wang, L., La Frano, M.R., Liang, A. 2017. Dose-related liver injury of Geniposide associated with the alteration in bile acid synthesis and transportation. Scientific Reports. 7:8938.
Krishnan, S., Tryon, R.R., Agrawal, K., Welch, L.C., Horn, W.F., Newman, J.W., Keim, N.L. 2018. Structural equation modeling of food craving across the menstrual cycle using behavioral, neuroendocrine, and metabolic factors. Physiology and Behavior. 195:28-36.
Forester, S.M., Widaman, A.M., Krishnan, S., Witbracht, M.G., Horn, W.F., Laugero, K.D., Keim, N.L. 2018. A clear difference emerges in hormone patterns following a standard mid-day meal in regular breakfast eating or breakfast skipping young women. Journal of Nutrition. 148(5):658-692.
Ghoshal, S., Stevens, J.R., Billon, C., Giradet, C., Situala, S., Leon, A.S., Rao, D., Skinner, J.S., Rankinen, T., Bouchard, C., Nunez, M.V., Stanhope, K.L., Howatt, D.A., Daugherty, A., Zhang, J., Schuelke, M., Weiss, E.P., Burris, T.P., Havel, P.J., Butler, A.A., Bennett, B.J., Sethupathy, P. 2017. Adropin: an endocrine link between the biological clock and cholesterol homeostasis. Molecular Metabolism. 8:51-64.
Price, C.A., Argueta, D.A., Medici, V., Bremer, A.A., Lee, V., Nunez, M.V., Chen, G.X., Keim, N.L., Havel, P.J., Stanhope, K.L., Dipatrizio, N.V. 2018. Plasma fatty acid ethanolamides are associated with postprandial triglycerides, ApoCIII and ApoE in humans consuming high fructose corn syrup-sweetened beverage. American Journal of Physiology - Endocrinology and Metabolism. 315(2):E141-E149.
Krishnan, S., Adams, S.H., Allen, L.H., Laugero, K.D., Newman, J.W., Stephensen, C.B., Burnett, D.J., Witbracht, M.G., Welch, L.C., Que, E.S., Keim, N.L. 2018. Impact of an 8-week controlled feeding trial based on the Dietary Guidelines for Americans on cardiometabolic health indices. American Journal of Clinical Nutrition. 108(2):266-278.
Agrawal, K., Hassoun, L.A., Foolad, N., Pedersen, T.L., Sivamani, R.K., Newman, J.W. 2018. Effects of atopic dermatitis and gender on sebum lipid mediator and fatty acid profiles. Prostaglandins Leukotrienes and Essential Fatty Acids. 134:7-16. https://doi:10.1016/j.plefa.2018.05.001.
Agrawal, K., Waller, J.D., Pedersen, T.L., Newman, J.W. 2017. Effects of stimulation technique, anatomical region and time on human sweat lipid mediator profiles. Prostaglandins & Other Lipid Mediators. 134:84-92.
Shearer, G.C., Borkowski, K., Puumala, S.L., Harris, W.S., Pedersen, T.L., Newman, J.W. 2017. Abnormal lipoprotein oxylipins in metabolic syndrome and partial correction by omega-3 fatty acids. Prostaglandins Leukotrienes and Essential Fatty Acids. 128:1-10.
Lafrano, M.R., Hernandez-Carretero, A., Weber, N., Borkowski, K., Pedersen, T.L., Newman, J.W., Osborn, O. 2018. Diet induced-obesity and weight loss alter bile acid profiles and gene expression in insulin target tissues. Nutrition Research. 46:11-21.
Hernandez-Carretero, A., Weber, N., La Frano, M.R., Ying, M., Lantero Rodriguez, J., Sears, D.D., Wallenius, V., Borgeson, E., Newman, J.W., Osborn, O. 2017. Obesity-induced changes in lipid mediators persist after weight loss. International Journal of Obesity. 46:11-21.
Coffey, A.R., Smallwood, T.L., Albright, J., Hua, K., Kanke, M., Pomp, D., Bennett, B.J., Sethupathy, P. 2017. Systems genetics identifies a co-regulated module of liver microRNAs associated with plasma LDL cholesterol in murine diet-induced dyslipidemia. PLoS Genetics. 49(11):618-629.
Barrington, W.T., Wulfridge, P., Gunaratna, R.T., Rojas, C.M., Howe, S.Y., Perry, A., Hua, K., Hansen, K.D., Fuchs-Young, R., Bennett, B.J., Pomp, D., Feinberg, A.P., Threadgill, D.W. 2018. Improving metabolic health through precision dietetics in mice. Genetics. 208:399-417.
Beccarelil, L.M., Scheer, R.E., Newman, J.W., Borkowska, A.G., Gray, I.J., Linnell, J.D., Keen, C., Young, H. 2017. Associations among fatty acids, desaturase and elongase, and insulin resistance in children. Journal of American College of Nutrition. 37:44-50.
Agrawal, K., Sivamani, R., Newman, J.W. 2018. Non-invasive profiling of sweat-derived lipid mediators for cutaneous research. Skin Research and Technology. 58:188-195. https://doi: 10.1194/jlr.M071738.
Agrawal, K., Bosviel, R., Piccolo, B.D., Newman, J.W. 2018. Oral ibuprofen differentially affects plasma and sweat lipid mediator profiles in healthy adult males. Prostaglandins & Other Lipid Mediators. 137:1-8.
Killion, E.A., Reeves, A.R., El Azzouny, M.A., Yan, Q., Surujon, D., Griffin, J.D., Bowman, T.A., Wang, C., Matthan, N.R., Klett, E.L., Kong, D., Newman, J.W., Han, X., Lee, M., Coleman, R.A., Greenberg, A.S. 2018. A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction. Molecular Metabolism. 9:43-46.