Location: Obesity and Metabolism Research2012 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 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.
1. 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.
2. Intermediary metabolism of sugar & fats. Blood metabolite analyses pointed to perturbed amino acid metabolism in obese insulin-resistant and diabetic states. Also, enzymes associated with select amino acid breakdown 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 energy, and changes in the gut microbe signature, underlie health phenotypes in response to diet.
3. 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 and salivary hormones. Thus, even in very young children a shift from executive to more emotional decision-making may promote excess calorie consumption.
4. 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. It was found that individuals who skipped breakfast consistently were more insulin-resistant than their breakfast-eating counterparts. This demonstrates that habitually omitting breakfast is related to compromised insulin action, a risk factor for type 2 diabetes and impaired blood sugar regulation.
5. 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. The efficiency of omega-3 fatty acid consumption in regulating changes in beneficial lipids in blood components were found to decrease as a person’s 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.
6. 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 component 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.
7. Lipid phenotyping to assess metabolic health. Obesity and type 2 diabetes are often coincident conditions making the segregation of their metabolic consequences difficult. In a study comparing overweight African-American women with and without type 2 diabetes, it was discovered that independent of weight, diabetes elevated blood plasma free fatty acids, increased markers of hepatic lipogenesis, decreased markers of very long chain fatty 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 compounds circulating in blood. The application of “lipidomics” provides a means to directly assess the metabolic health of overweight individuals, going beyond the traditional determination of blood glucose alone.
8. Zinc and blood glucose control. Although type 2 diabetes is often associated with obesity, it can occur in lean subjects. Possible links to 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 in the mice despite that they remained lean on a high fat diet. The study revealed that zinc, an essential micronutrient, is an important player in maintaining normal secretion and function of the blood glucose-regulating hormone insulin.
9. Zinc and glucose uptake in muscle. Muscle tissue requires a constant source of energy, including glucose, to function optimally. Micronutrient status may impinge upon pathways involved in tissue glucose uptake. A rat 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.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.