1a. Objectives (from AD-416):
ENERGY METABOLISM: 1: Determine the effects of specific dietary composition factors, including macronutrient type, fiber & food form on hunger, satiety & energy regulation. 2: Demonstrate effective methods for sustainable weight control & prevention of obesity in adult population groups spanning a range of ages & demographics. 3: Develop new methodology for improving the accuracy & precision of assessment of energy & nutrient intakes & energy requirements in adults. OBESITY AND METABOLISM: 1: Determine the mechanistic roles of the intestinal and hepatic proteins ACSL5 and plin2 in fatty acid metabolism, especially in delivery of dietary triacylglycerol to tissues and tissue lipogenic metabolism. 2: Determine the physiologic actions and consequences of ACSL5 in diet-induced obesity and obesity associated metabolic complications. BODY COMPOSITION: 1: Develop and validate stable isotope methodology to that can be utilized to investigate energy regulation related to sarcopenic obesity and frailty in the elderly. 2: Validate energy dispersive X-ray fluorescence methodologies for studying the prevalence of zinc deficiency and implications of zinc deficiency in the elderly.
1b. Approach (from AD-416):
LAB NAME: ENERGY METABOLISM The mission of the Obesity and Energetics Laboratory is to understand the effects of lifestyle factors on energy metabolism and weight regulation. Our research examines dietary and behavioral variables that influence both energy intake and metabolism throughout the adult lifecycle, and our focus is to develop and test effective lifestyle interventions for implementing sustainable, healthy weight control at all ages. Studies in our laboratory include in-depth biological examinations of the impact of different dietary factors on biochemical and neurological factors involved in energy regulation and body composition, chemical studies of food composition, and randomized controlled trials testing practical interventions that can be scaled for population-wide benefits. LAB NAME: OBESITY AND METABOLISM To address the role of acyl CoA synthetase 5 (ACSL5) and perilipin 2 (plin2) in intestinal enterocytes and hepatocytes we have generated conditional lines of knockout of ACSL5 and plin2 mice allowing us to disrupt in a tissue specific manner. We will investigate the physiological effects of ablation of ACSL5 and plin2 in mouse hepatocytes and enterocytes and the response to a high caloric diet in vivo. In these animal studies we will determine body composition, energy expenditure, insulin glucose homeostasis, fat absorption, hepatic steatosis, and in liver and intestine tissues gene expression will be determine. In isolated hepatocytes studies in our mice we will triglyceride (TG) accumulation, and TG oxidation. The studies in this project will provide novel insights that will allow researchers to direct therapeutic strategies to protect against the development of obesity and associated complications. LAB: BODY COMPOSITION Simple monitoring of isotope clearance in breath CO2 can provide detailed information on the metabolism of labeled food and help us understand the connection between food composition and energy management. Our approach includes the use of a single stable isotope administration (C-13 palmitic acid or carbohydrate) and monitoring its disappearance in breath CO2 for several days. We use both mathematical modeling and clinical validation. Repeated measurements of C-13 in breath CO2 provide us with a profile of the timing and efficiency of oxidation of the labeled fuel. The development and validation of new tools for field use include a new portable analytical device that can measure zinc content in fingernail clippings. The methodology used is non-destructive energy dispersive X-ray fluorescence (XRF). Preliminary results show that zinc measurement in protein (fingernails) is a better indicator for zinc status than zinc measurements in plasma. This is because plasma values can be easily affected by resent food intake or infection. This methodology will be tested in nursing home residents. It will become an addition to a set of portable devices that we have developed for the evaluation of nutrition status, hydration, and frailty in the field. The instruments are designed to evaluate status as well as to assess the efficacy of treatments and nutrition programs in older adults.
3. Progress Report:
ENERGY METABOLISM LAB: The Energy Metabolism Laboratory continued its projects investigating factors determining successful weight control in adults of different ages. The laboratory has had considerable success in all projects. For Objective 1 we have completed analyses of our randomized trial of whole grain and refined grain foods and are about to submit a paper providing additional justification for whole grains in the diet of Americans. We also published a paper analyzing the effect of high- versus low-glycemic load diets on metabolic rate and reported no difference between treatments. This is an important paper because it was a carefully conducted study with provided food that contradicted previous suggestions from a less carefully controlled study published previously by another group. For Objective 2 we have recruited our worksites and employees for our worksite weight management study. In addition, we have an additional randomized controlled trial that relates to this objective which was funded by the Department of Defense. We are conducting the trial in adult dependents of active duty military personnel in multiple bases around New England currently and are about to expand to Colorado and Kansas, making this a study of truly national scope. For Objective 3 we completed a multisite study comparing the energy content of restaurant meals from 3 regions of the country and 9 ethnic meal types and published the study along with policy suggestions for how to facilitate a reduction in the energy content of this important source of nutrition for Americans. This data extends our previous finding that restaurant meals have excessive calories and contribute to the obesity epidemic. OBESITY LAB: Over the last year we have investigated the role of acyl CoA synthetase 5 (ACSL5) protein in intestinal metabolism using mice in which ACSL5 was specifically ablated within intestinal enterocytes and another line of mice in which ACSL5 was specifically ablated in hepatocytes (liver cells). Our studies have demonstrated that deficiency of ACSL5 within hepatocytes of mice ingesting a low fructose, low fat diet does not alter body fat accumulation, energy metabolism or systemic lipid metabolism. We have also demonstrated that a high fructose diet increases the expression of hepatic ACSL5. However when we fed mice, which did not express ACSL5 within hepatocytes, a high fructose diet we observed no changes in the accumulation of triacylglycerol in the liver. Thus, hepatic ACSL5 expression does not appear to be necessary for accumulation of liver triacylglycerol during ingestion of a high fructose diet. Our data indicates that deficiency of ACSL5 within intestinal enterocytes results in increased hepatic expression of the hormone fibroblast growth factor (FGF) 21. FGF21 is then secreted into the circulation and acts on white adipocytes to increase the expression of uncoupling protein 1 in white adipocytes and consequently promotes increased rates of whole body energy expenditure and reduced adiposity. Also we have observed that reductions in ACSL5 expression reduces the rate of absorption of dietary fat.
1. Excessive calories in non-chain restaurant meals. Obesity is a serious health crisis in the U.S., and is raising health care costs, which negatively impact the competitiveness of US companies. Understanding the causes is important to help drive effective policy initiatives. Tufts University researchers at USDA in Boston, Massachusetts, completed a multi-site trial measuring the calorie content of meals from restaurants that will not be required to report nutrition when the new labeling requirement takes effect. They showed excessive portion sizes in more than 90% of restaurants, with some meals providing more than a whole day’s worth of calories. These excessive portions promote overeating, and policy suggestions are recommended based on this work to help reduce the current incentive of restaurants to overfeed their customers. (ENERGY METABOLISM LAB)
2. Calorie restriction regimen is safe and effective. Improving health span so that old age is not accompanied by many years of disability and poor health is an important goal of aging research programs worldwide. Tufts University researchers at USDA in Boston, Massachusetts, were part of a multi-site national team that completed a landmark 2-year randomized controlled trial of human caloric restriction showing beneficial effects of caloric restriction across metabolic and psychological health parameters. Moreover, the program was successful in achieving 10% reduction in calorie intake over 2 years, the first demonstration that this is possible without an increase in hunger or detrimental effects on mood or quality of life. Thus, calorie restriction is feasible and without apparently harmful side effects, and can be recommended for long-term facilitation of good health into old age. (ENERGY METABOLISM LAB)
3. Low glycemic index carbohydrates do not beneficially influence metabolic rate. Reducing the obesity epidemic is one of the most important health challenges of our time. Tufts University researchers at USDA in Boston, Massachusetts, have evaluated whether low glycemic index carbohydrates influence metabolic rate, which is a research topic of intense controversy that relates to what type of dietary recommendations are optimal for weight management. The team showed no effect of low glycemic index carbohydrates compared to high glycemic index ones, refuting a previous study and providing further support for current dietary guidelines, which do not emphasize glycemic index. (ENERGEY METABOLISM LAB)
4. Ablation of adipocyte acyl CoA synthetase 4 protects against diet-induced obesity, liver fat accumulation and insulin resistance. Alterations in fat cell metabolism with obesity are thought to promote increases in body fat and the risk of developing type 2 diabetes mellitus. Tufts University researchers at USDA in Boston, Massachusetts, demonstrated that when mice which were genetically modified to not express the protein acyl CoA synthetase 4 within fat cells, and were fed a high caloric diet, they demonstrated significant protection against the accumulation of body fat and metabolic complications that predispose one to the development of diabetes. Our studies revealed that absence of acyl CoA synthetase 4 within fat cells increased the ability of the body to burn calories and specifically increased the ability to metabolize fat within fat cells. The discovery that reduced expression of acyl CoA synthetase 4 in fat cells increases the ability of the body to metabolize fat provides researchers with a therapeutic target to develop diets and drugs to ameliorate obesity and its complications such as diabetes. (OBESITY LAB)
5. Significant Activities that Support Special Target Populations:
Bowman, T.A., O'Keefe, K.R., D'Aquila, T., Yan, Q., Griffin, J.D., Killion, E., Mashek, D.G., Buhman, K.K., Greenberg, A. 2016. Acyl CoA synthetase 5 (ACSL5) ablation in mice increases energy expenditure and insulin sensitivity and delays fat absorption. Molecular Metabolism. 5(3):210-220. doi: 10.1016/j.molmet.2016.01.001.