2006 Annual Report 1.What major problem or issue is being resolved and how are you resolving it (summarize project aims and objectives)? How serious is the problem? Why does it matter? More than 60 percent of adults in the United States (US) are classified as overweight or obese. Obesity is one of the major public health problems in the US today and contributes significantly to increased disease, illness and premature death. Obesity is a problem now in people of all ages. The Determination of Energy Regulation in Aging CRIS is aligned with the goals of NP107 Human Nutrition, and focuses its research on understanding the etiology of body fat gain and muscle loss throughout adult life, and improving dietary-based methods for prevention and treatment in adults ranging in age from young to elderly. The Energy Metabolism Laboratory (EML) focuses on the energy metabolism of normal adults; the effects of aging on energy and substrate regulation; and dietary and other factors influencing energy regulation. The work of our laboratory is used by the USDA, the Institute of Medicine and other national and international bodies for the development of dietary recommendations. Our work is also used by the scientific community to enhance the progress of nutrition research and is of substantial interest to the general public and media. There are three separate, but related lines of research within this CRIS: the Energy Metabolism Laboratory is the first as described above. The Obesity and Metabolism Laboratory (OML) conducts investigations on the metabolic factors related to the role of adipose tissue in whole body energy regulation. Specifically, scientists are defining the role of perilipins - proteins that coat intracellular stores of fat in adipocytes (fat cells) and are involved in regulating the breakdown of fat within adipocytes. This work contributes to the systematic study of how the body ages with respect to energy regulation and sarcopenia (loss of muscle and function with age) by defining the role of fat cells in energy regulation at different stages of life. The Body Composition Laboratory seeks to increase the understanding of mechanisms leading to the age-related loss of muscle mass and dehydration and to develop appropriate interventions that will help maintain and improve quality of life in the elderly. We are working to:. 1)adapt newly developed technologies to create, validate and use portable body composition methods for monitoring homebound and institutionalized elderly;. 2)use a new approach to dual energy x-ray absorptiometry to develop a reference method for high precision body composition analysis to replace existing technology, which focuses on bone density measurements;. 3)define the relationship between nutritional status, frailty, cognitive function and hydration status and validate methods to monitor and manage dehydration and frailty in nursing home elderly; and. 4)develop an in vivo whole-body protein status monitor based on minimally invasive fast neutron activation. Results from this research will contribute to the systematic study of sarcopenia (loss of muscle and function with age) by providing body composition tools and methods specifically designed for the elderly and will also define specific measurable outcomes of nutritional interventions. 2.List by year the currently approved milestones (indicators of research progress) Energy Metabolism Laboratory (EML) 51000 -061-01A EML Objective 1: To develop two healthy hypocaloric diets consistent with current dietary recommendations and compare them for their ability to promote long-term calorie restriction (CR) leading to body weight and fat losses over one year in overweight men and women. EML Objective 2: To test the hypothesis that there are metabolic and anti-aging benefits of long-term (2-year) CR in overweight men and women that are equivalent to the benefits seen in animal models. We hypothesize that there will be no significant adverse effects of long-term CR that would preclude its use in healthy adults. EML 2005 1. Develop two healthy hypocaloric diets consistent with current dietary recommendations that span the range of recommended macronutrient intakes. Objective 1. 2. Recruit 44 human subjects for a 1-year study comparing the two different diets. Objective 1. 3. Enroll the 44 subjects in research study to compare the two diets for their ability to promote long-term caloric restriction and weight loss. Objective 1. EML 2006 1. Complete study of the effect of two diets on their ability to promote caloric restriction and weight loss. Objective 1. 2. Conduct data analyses comparing two diets for weight loss and body composition loss. Objective 1. 3. Conduct data analyses for metabolic predictors of weight loss. Objective 1. 4. Prepare manual of procedures for randomized clinical trial on the effects of caloric restriction on biological markers of aging. Objective 2. EML 2007 1. Conduct data analyses for psychological predictors of weight loss and cognitive effects of caloric restriction. Objective 1. 2. Conduct data analyses for effects of caloric restriction and dietary composition on metabolic efficiency. Objective 1. 3. Recruit first 50 percent of the human subjects for 2-year study of the effects of caloric restriction on biological markers of aging and enroll them in study of caloric restriction. Objective 2. EML 2008 1. Conduct data analysis on accuracy of Dietary Reference Intakes (DRIs) for determining energy requirements compared to doubly labeled water assessments of energy intake. Objective 1. 2. Conduct data analysis on the effect of caloric restriction and dietary composition on physical activity, body temperature and quality of life. Objective 1. 3. Recruit second 50 percent of the human subjects for 2-year study of the effects of caloric restriction on biological markers of aging. Objective 2. EML 2009 1. Continue outcome assessments in study of caloric restriction and biological markers of aging (primary outcomes are weight, body composition, dietary intake, insulin sensitivity, blood pressure and lipids and markers of immune function and oxidative stress). Objective 2. 2. Analyze baseline data from study of caloric restriction and biological aging. Objective 2. Obesity and Metabolism Laboratory (OML) 51000-061-02A OML Objective 1: To determine role and molecular mechanisms by which perilipin, a protein that coats stored fat in fat cells (adipocytes) regulates fat breakdown (lipolysis) and fat cell storage in adipocytes. OML Objective 2: To determine the mechanism(s) by which the absence of perilipin expression in mouse adipocytes (perilipin null mice) results in resistance to diet and genetic-induced obesity. OML Objective 3: To define how age, sex, genetic background and diet alters the susceptibility of perilipin null and wild-type mice to the development of insulin resistance and diabetes. To do this we will investigate female and male mice, young and old mice, and mice with different genetic background, comparing mice that lack perilipin (peri null mice) and normal or wild-type mice. OML 2005 1. Determine the differences in adipocyte lipolysis in peri null and wild-type mice. Objective 1 2. Establish stable adipocyte cell lines. Objective 1 3. Determine serum adiponectin levels in peri null and wild-type mice. Objective 2 4. Determine the role of perilipin expression and adipocyte metabolism in modulating adipose tissue macrophage function and expression in humans as well as animal models of obesity. Objective 3 5. Generate backcrossed peri null mice by separately mating into C57BL6J. Objective 3 OML 2006 1. Determine the role of perilipin expression and phosphorylation state in regulating hormone-sensitive lipase (HSL) translocation (movement of HSL from cytoplasm to the surface of intracellular fat droplets where fat is stored) and lipolysis. Objective 1 2. Determine how perilipin expression and phosphorylation state regulate thermogenesis in brown adipose tissue. Objective 2 3. Determine how estrogen regulates perilipin expression, adipokine function, inflammatory tone, and adipocyte metabolism. Objective 3 OML 2007 1. Determine AMPK activation state in adipose tissue, muscle, and skeletal muscle of wild-type and perilipin null mice. Objective 2 2. Determine how aging alters adipocyte metabolism, adipokine production, and adipose tissue macrophage and preadipocyte function in wild-type and perilipin null mice. Objective 3 OML 2008 1. Define how aging affects measures of insulin/glucose homeostasis, energy metabolism, and body composition in wild-type and perilipin null mice. Objective 3 OML 2009 1. Determine how a combined high fat/high sucrose diet affects adipose tissue metabolism and inflammation and measures of systemic metabolism in young and old wild-type and perilipin null mice. Objective 3 Body Composition Laboratory (BCL) 51000-061-03A BCL Objective 1: Adapt newly developed technologies to create, validate and use portable body composition methods for monitoring homebound and institutionalized elderly. BCL Objective 2: Use a new approach to dual energy x-ray absorptiometry to develop a reference method for high precision body composition analysis to replace existing technology, which focuses on bone density measurements. BCL Objective 3: Define the relationship between nutritional status, frailty, cognitive function and hydration status. Validate methods to monitor and manage dehydration and frailty in nursing home elderly. BCL Objective 4: Develop an in vivo whole-body protein status monitor based on minimally invasive fast neutron activation. BCL 2005 1. Continuation of pilot project entitled “Hydration Status and Frailty in Nursing Home Residents”. Includes recruitment of human subjects, hydration and body composition measurements and comparison between methods and measures of mental capacity and frailty. Objective 3 2. Mechanical design of the detector support system for the nitrogen monitor, design of the initial acquisition system and testing of the prototype detector. Objective 4 BCL 2006 1. Completion of the technical development of the hand-held absorptiometer, an instrument for bedside analysis of soft tissue composition designed for monitoring nutrition status in the field. Objective 1 2. Determine the optimal photon energy for soft tissue analysis as a function of tissue composition and thickness. Objective 2 3. Determine the relationship between hydration status and cognitive function in nursing home residents. Objective 3 BCL 2007 1. Completion of hydration and frailty in nursing home residents. The results will be used to design a monitoring system for assisted living and nursing homes. Objective 3 2. Evaluate the capability of multi-frequency bioelectrical impedance to measure extracellular water space in nursing home residents. Objective 3 BCL 2008 1. Validation of the portable, bedside x-ray absorptiometer against mid-thigh computerized tomography. Objective 1 2. Absolute neutron output measurements of the HNRCA neutron generator. Modifications to increase its neutron output so that protein measurements are feasible. Objective 4 3. Installation of new detector system in the whole body counter. Objective 4 BCL 2009 1. Field use and validation of portable X-ray absorptiometer. Objective 1 2. Design of full size absorptiometer with farm animals (Beltsville). Objective 2 3. Completion and data analysis from hydration study with nursing home residents. Objective 3 4. Calibration and validation of protein monitor. Objective 4 4a.List the single most significant research accomplishment during FY 2006. Dietary Carbohydrate Intake, Insulin Secretion and Weight Loss. The Energy Metabolism Laboratory has found that insulin secretion in response to a standard oral glucose tolerance tests predicts whether an individual will lose more weight on a low fat versus higher fat diet. Both diets tested approximated the range of healthy dietary compositions recommended, however one provided 60% of energy from carbohydrate and the other provided 40% (with corresponding more protein and more fat). Individuals with higher insulin secretion were able to lose significantly more weight in a 6-month provided food program when they consumed a diet lower in carbohydrate content. This is an important finding as it is the first study to identify an individual trait (in this case insulin secretion, which can be easily measured) that helps determine which type of weight loss diet is more likely to be successful in a particular individual. This accomplishment is aligned with NP107 Human Nutrition Program Component. 6)Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle. 4b.List other significant research accomplishment(s), if any. Estrogen Activates Oxidative Pathways in Skeletal Muscle. The Obesity Metabolism Laboratory demonstrated that estrogen increases fat oxidation (pathways that burn fat) in skeletal muscle of mice by two separate mechanisms. Estrogen both activated genes involved in fat oxidation and also signals the cell to activate another pathway that increases fat oxidation. These observations provide new insights into how estrogen protects against menopausal complications such as diabetes and increased body fat. The discovery of these pathways will help researchers and individuals to devise strategies, including specific diets and exercise prescriptions that protect and/or ameliorate menopause related complications. This accomplishment aligns with National Program 107 – Human Nutrition program component 6: Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle. Determination of the Optimal Photon Energies for Composition Analysis of Soft Tissue. The Body Composition Laboratory has completed theoretical calculations and experimental verification on the optimal energy of photons to be used in the hand-held body composition x-ray caliper. The competing factors were that high energies have better penetration in tissue but show less sensitivity in identifying tissue composition. This finding will provide the technical foundation for the development of instruments, methods and programs designed to improve monitoring, safety and quality of independent living in the elderly. This accomplishment most closely aligns with National Program 107 – Human Nutrition - component 3: Nutrition Monitoring. Dietary Variety and Weight Loss in Old Age. The Energy Metabolism Laboratory has shown that low dietary variety in old age predicts low Body Mass Index (BMI), which is a predictor of poor outcome in old age. Using USDA national data we found that individuals who consumed a low variety of higher energy density food items had lower BMI. These results suggest that recommendations to elders to maintain dietary variety may be an important means by which undesirable weight loss can be prevented. Intervention studies are needed to confirm this observational finding. This accomplishment is aligned with NP107 Human Nutrition Program Component. 6)Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle. 4c.List significant activities that support special target populations. None. 4d.Progress report. None. 5.Describe the major accomplishments to date and their predicted or actual impact. The Energy Metabolism Laboratory has provided a unique series of experiments designed to understand changes in energy regulation with aging. The laboratory was the first to demonstrate impaired regulation of food intake in old age, a finding that has subsequently been confirmed by several research groups, and has found underlying metabolic reasons explaining the reduced regulation of food intake (e.g., higher circulating levels of postprandial glucose in the elderly that reduced perceptions of hunger). We have also examined the practical utility of measurements of reduced hunger and satiety for predicting undesirable weight loss. Our results are used by other scientists to develop future research programs by national and international dietary recommendation agencies (e.g., the USDA/DHHS Dietary Guidelines for Americans), and by the media to inform the general public of new findings relating to weight regulation and nutrition in old age. Our work has profound potential impact on the national obesity epidemic, since we are finding, over time, different ways to limit energy intake for prevention of weight gain and successful sustained weight loss. These results relate to National Program 107 – Human Nutrition, component 6: Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle. The major accomplishments over the life of the project for the Obesity Metabolism Laboratory include our research on the role of perilipin in regulating subcellullar localization and function of lipases. We have completed the generation of stable adipocyte lines that do not express perilipin. We have found that perilipin regulates the translocation of hormone-sensitive lipase (HSL) to the surface of stored fat. Lipolysis is blocked when perilipin cannot be phosphorylated by hormones. However, HSL translocates to the surface of lipid droplets in fat cells that contain an unphosphorylated perilipin. This data, for the first time demonstrate that HSL translocation is important for stimulated lipolysis but is not sufficient for fat breakdown. Our laboratory demonstrated that estrogen increases fat oxidation (pathways that burn fat) in skeletal muscle of mice by two separate mechanisms. Estrogen both activated genes involved in fat oxidation and also signals the cell to activate another pathway that increases fat oxidation. These observations provide new insights into how estrogen protects against menopausal complications such as diabetes and increased body fat. The discovery of these pathways will help researchers, nutritionists, pharmaceutical companies, and individuals to devise strategies, including specific diets and exercise prescriptions, which protect and/or ameliorate menopause related complications. These accomplishments are aligned to National Program 107 – Human Nutrition, component 6: Prevention of Obesity and Disease: Relationship between Diet, Genetics, and Lifestyle The major accomplishment of the Body Composition Laboratory over the life of the project is the finding that hydration level is not related to cognitive function in elderly nursing home residents. This project was designed to study the mechanisms of dehydration and muscle loss in homebound and institutionalized elderly. Preliminary analysis of pilot data from a study conducted in two Boston area nursing homes showed no correlation between body hydration and obtained cognitive function score. This finding indicates that it is the quality of care rather than thirst or mental status that regulates water intake in a tightly controlled nursing home environment. This is a significant early result of our study indicating that close monitoring of hydration in the elderly will be most beneficial in assisted and independent living environments where dehydration and sarcopenia can progress undetected. We will modify the recruitment criteria for the expanded phase of this study to utilize this early finding. This accomplishment relates to National Program 107 – Human Nutrition component 3 - Nutrition Monitoring. 6.What science and/or technologies have been transferred and to whom? When is the science and/or technology likely to become available to the end-user (industry, farmer, other scientists)? What are the constraints, if known, to the adoption and durability of the technology products? The research findings have been presented to the scientific community at a number of meetings and have also been published in prestigious peer-reviewed scientific journals. Results of this research also reach the public directly through press releases, and the print and electronic media. These data will be used by scientists conducting nutrition-related research, by the food industry, and by consumers. The Obesity Metabolism Laboratory has filed for the following patent with Dr. Jose Ordovas of the HNRCA Nutrition and Genomics Laboratory (CRIS 51520-010-01A), entitled: Genetic Markers for Obesity; and in 2006: Estrogen metabolite regulation of AMPK activated protein kinase. We were awarded U.S. Patent # 6,897,019 “Methods for Treating and Preventing Insulin Resistance and Related Disorders.” 7.List your most important publications in the popular press and presentations to organizations and articles written about your work. (NOTE: List your peer reviewed publications below). Drs. Roberts, Greenberg and Kehayias gave 17 invited lectures at scientific meetings and to general audiences about their research results. Susan Roberts – Invited Lectures 1. April 1-5, 2006 - Council of the American Society for Nutritional Sciences, Symposium, Caloric Restriction and Aging In Humans, for presentation in San Francisco, CA as part of the experimental Biology 2006 Annual Meeting. 2. June 2-6, 2006 - Pre-meeting workshop on "Caloric Restriction" at the 2006 meeting of the American Aging Association, Boston, MA. 3. June 6, 2006 - CALERIE Imaging Workshop on Body Composition, Crowne Plaza Hotel 1605 Broadway, New York, NY. Andy Greenberg – Invited Lectures 1. Adipocyte Necrosis and Macrophage Function in Obesity, North American Association for the Study of Obesity, 10/2005. 2. Adipocyte Necrosis and Macrophage Function in Obesity, Tufts-New England Medical Center Endocrine Grand Rounds, 11/2005. 3. Through Obesity and Thin: Metabolic Disease, a New Paradigm and Disease for the 21st Century. Tufts Research Day, 12/2005. 4. Adipocyte Necrosis and Macrophage Function in Obesity. University of Maryland School of Medicine, 12/2005. 5. A Role for Estrogen in Regulating Obesity and Metabolism. Endocrinology Division, University of Pittsburgh, 03/2006. 6. Adipocyte Necrosis, Possible Role in Obesity Associated Alterations in Adipose Tissue Inflammation. Department of Nutrition Seminar, University of North Carolina at Chapel Hill, 03/2006. 7. Role of Estrogen in Systemic Metabolism. Endocrinology Division, University of Maryland, Baltimore, 03/2006. 8. Metabolic Complications of Obesity: An Epidemic for the 21st Century. Medical Grand Rounds, Tufts-New England Medical Center, 04/2006. 9. Estrogen Regulation of Adipocyte and Systemic Metabolism: Society for Women’s Research, Isis Fund Network on Metabolism, Washington D.C., 05/2006. 10. Symposium invited talk: Necrosis and Adipocytes in Obesity. American Diabetes Association Scientific Sessions, Washington D.C., 06/2006 Joseph Kehayias – Invited Lectures 1. Boston University, School of Dental Medicine, Boston, MA, November 16, 2005. Body Composition Measurement in Nutrition Research. 2. Edith Nourse Rogers VA Hospital, Bedford, MA, December 1, 2005. New Body Composition Methods for Bedside Evaluation of Nutritional Status, Dehydration, and Frailty. 3. National Congress on Nutrition and Dietetics, Athens, GR, December 9, 2005. Modern Aspects on Body Composition Assessment: Emphasis on Muscle Mass. 4. National Science Foundation/National Institutes of Health Joint Workshop on Bioengineering Approaches to Energy Balance and Obesity, Body Composition Assessment in the Management of Sarcopenic Obesity. Arlington, VA, June 6-7, 2006. Susan Roberts – Press Oct 31, 2005 Vol. 152, No. 9 http://www.fortune.com/fortune/print/0,15935,1119285,00.html FORTUNE BREAKAWAY BRANDS How to Build a Breakaway Brand How ten companies, making products from drills to waffles, took good brands and made them much, much better. By Al Ehrbar December 26, 2005 Time U.S. Edition SECTION: YOUR TIME/HEALTH; Pg. 184 Vol. 166 No. 26 Persons of the Year LENGTH: 424 words HEADLINE: Resolutions BYLINE: Christine Gorman April 17, 2006 The Milwaukee Journal Sentinel by John Fauber, Milwaukee Journal Sentinel A curb on calories: Long-term studies begin to show positives of restrictive eating July 18, 2006; Wall Street Journal HEALTH JOURNAL By TARA PARKER-POPE The 100-Calorie Solution: Smaller Snacks May Not Lead to Smaller Waistlines Page D1 Andy Greenberg – Press News and Events – United States Department of Agriculture, Agricultural Research Service http://www.ars.usda.gov/is/pr/2005/051021.htm Estrogen and Exercise Promote Leanness in Similar Ways October 21, 2005 By Rosalie Bliss The Boston Globe Mind Your Metabolism Weight gain and a loss of lean muscle mass often start in your 30s – but you can fight both with these measures. December 4, 2005 By Julia Tolliver Maranan News and Events – United States Department of Agriculture, Agricultural Research Service http://www.ars.usda.gov/is/pr/2005/051227.htm New Findings on Low-Glycemic-Load Diets for Weight Loss December 27, 2005 By Rosalie Bliss Agricultural Research Inflammatory News about Fat Cells March 2006; page 4 By Rosalie Bliss Agricultural Research Genetic Variations Affect Obesity-Related Risks March 2006; page 5 By Rosalie Bliss Time Magazine http://www.time.com/time/archive/preview/0,10987,1200765,00.html Does My Diet Fit My Genes? June 12, 2006; pages 69-70 By Christine Gorman