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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Research Project #427820

Research Project: Energy Regulation and Obesity

Location: Jean Mayer Human Nutrition Research Center On Aging

2018 Annual Report

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.

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.

Progress Report
ENERGY METABOLISM LAB: In addition to describing the papers published in our accomplishments, the laboratory has been working to complete its clinical trials, which are designed to test whether more effective and sustainable methods for weight loss can be achieved in challenging populations, including military families and worksite employees. Our work in military families, partially funded by a partnership with Department of Defense scientists, is going well, and we completed study enrollment in December 2017. This study is the first of its kind to attempt to develop a successful and scalable method for weight management in military families. We follow best practices by having separate teams for intervention delivery and outcomes with data accessible only by the outcomes team. In April 2018 in a presentation to the Department of Defense of weight data that was not broken down by randomization, we showed clinically significant weight loss that is higher than previous weight loss results in similar populations. Work is now ongoing in 5 states and all participant data will be collected by December 2018 (Massachusetts, Connecticut, Colorado, Kentucky and New York). Our second randomized trial is a large 12-site worksite intervention being conducted in Massachusetts, in which sites are randomized to an active control (both weight management and healthy living interventions are offered on a non-randomized basis) or a wait-listed control. All study measurements were completed in February 2018, and we are currently completing data entry and data cleaning prior to analysis, which will occur during the coming year. As in our military study, we have followed best practices by having separate teams for intervention delivery and outcomes with data accessible only by the outcomes team. Progress was also made in our International Obesity Consortium studies. We have completed data analysis for a study of restaurant meals in our international sites, are working with our collaborating sites in 4 countries to prepare the data for publication. OBESITY AND METABOLISM LAB: We continued our studies on mice in which the expression of acyl CoA synthetase 5 (ACSL5) ablated within intestinal enterocytes of mice. Previous studies had demonstrated that mice with intestinal deficiency of ACSL5 when fed a high fat diet were significantly protected against the development of diet induced obesity. Our previous hypothesis was that intestinal ACSL5 protected mice against diet-induced obesity was primarily due to increased energy expenditure. However, studies over the last year demonstrated that the intestinal deficiency of ACSL5 resulted in significantly reduced ingestion of the high fat diet. Additional studies demonstrated that ACSL5 intestinal deficiency significantly increased circulating levels of the intestinal hormone, glucagon-like peptide 1 (GLP1). GLP-1 has been demonstrated to increase satiety by several mechanisms and likely a significant part of the observed increase in satiety with ACSL5 intestinal deficiency. We have also generated mice in which the protein, perilipin 2 (plin2), was specifically ablated within hepatocytes of mice. On a low fat diet, mice with hepatic deficiency of plin2 demonstrated a trend towards hepatic accumulation of triacylglycerol. While on a high fat diet, mice with hepatic deficiency of plin2 were significantly protected against the development of hepatic steatosis but were not protected against alterations in insulin/glucose homeostasis.

1. ENERGY METABOLISM LAB: Majority of popular meals at independent and small-chain restaurants exceed calorie requirements. Independent and small-chain restaurants, defined as operating fewer than 20 sites, are currently exempt from a federal law that requires nutritional information be provided to customers. ARS-funded researchers in Boston, Massachusetts conducted a multi-site study of the calorie content of 362 popular meals served by a variety of independent restaurants in Boston, Little Rock and San Francisco and determined that 92 percent of these meals exceeded calorie requirements for a single meal. Combined with studies that show people do not reduce their other daily food intake to compensate for eating in restaurants, these findings provide evidence of a common practice that is contributing to the national obesity epidemic. These findings may lead to greater awareness of the high calorie content of independent restaurant meals, and result in diners making more informed choices and policymakers including independent restaurants in laws requiring nutritional information to be posted.

2. OBESITY AND METABOLISM LAB: Absence of a specific protein in intestine significantly protects against obesity and associated metabolic complications. Previous studies have suggested that alterations in intestinal metabolism are involved in the development of obesity which increases the risk of developing type 2 diabetes. ARS-funded researchers in Boston, Massachusetts demonstrated that mice genetically modified to not produce the protein acyl CoA synthetase 5 in the intestine did not develop diet-induced obesity. These mice also had increased circulating levels of the intestinal hormone glucagon-like peptide 1 (GLP-1) which is known to reduce hunger. Analogues of GLP-1 have been approved in humans for treatment of type 2 diabetes and obesity. The discovery that reducing the production of intestinal acyl CoA synthetase 5 can promote satiety and reduce food intake may provide a new way to treat obesity and reduce the diabetes epidemic.

Review Publications
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. 9:43-56.
Hou, X., Zhang, Y., Li, W., Hu, A.J., Luo, C., Zhou, W., Hu, J.K., Daniele, S.G., Wang, J., Sheng, J., Fan, Y., Greenberg, A., Farmer, S.R., Hu, M.G. 2018. CDK6 inhibits white to beige fat transition by suppressing RUNX1. Nature Communications. 9:1023.
Kumari, Y.P., Roberts, S., Kahn, M.A., LaVertu, A.E., Das, S. 2016. Effectiveness of workplace weight management interventions: a systematic review. Current Obesity Reports. 5:298-306.
Urban, L.E., Weber, J.L., Heyman, M.B., Schichtl, R.L., Verstraete, S., Lowery, N.S., Das, S., Schleicher, M.M., Rogers, G., Economos, C., Masters, W.A., Roberts, S. 2016. Energy contents of frequently ordered restaurant meals and comparison with human energy requirements and US Department of Agriculture database information: a multisite randomized study. Journal of the Academy of Nutrition and Dietetics. 116(4):590-598.
D'Aguila, T., Sirohi, D., Grabowski, J.M., Hedrick, V.E., Paul, L.N., Greenberg, A., Kuhn, R.J., Buhman, K.K. 2015. Characterization of the proteome of cytoplasmic lipid droplets in mouse enterocytes after a dietary fat challenge. PLoS One. 10(5):e0126823.
Das, S.K., Roberts, S.B., Bhapkar, M.V., Villareal, D.T., Fontana, L., Martin, C.K., Racette, S.B., Fuss, P.J., Krauss, W.E., Wong, W.W., Saltzman, E., Pieper, C.F., Fielding, R.A., Schwartz, A.V., Ravussin, E., Redman, L.M. 2017. Body-composition changes in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE)-2 study: A 2-y randomized controlled trial of calorie restriction in nonobese humans. American Journal of Clinical Nutrition. 105:913–927.
Martin, C.K., Bhapkar, M., Pittas, A.G., Pieper, C.F., Das, S., Williamson, D.A., Scott, T., Redman, L.M., Stein, R., Gilhooly, C.H., Stewart, T., Robinson, L., Roberts, S.B. 2016. Effect of calorie restriction on mood, quality of life, sleep, and sexual function in healthy nonobese adults: the CALERIE 2 randomized clinical trial. Internal Medicine. 176(6):743-752.
Lytle, L.A., Nicastro, H.L., Roberts, S., Evans, M.R., Jakicic, J.M., Laposky, A.D., Loria, C.M. 2018. Accumulating Data to Optimally Predict Obesity Treatment (ADOPT) core measures: behavioral domain. Obesity. 26(2):S16-S23.
Racette, S.B., Rochon, J., Uhrich, M.L., Villareal, D.T., Das, S.K., Fontana, L., Bhapkar, M., Martin, C.K., Redman, L.M., Fuss, P.J., Roberts, S.B., Kraus, W.E. 2017. Effects of two years of calorie restriction on aerobic capacity and muscle strength. Medicine and Science in Sports and Exercise. 49(11):2240-2249.
Das, S., Mason, S.T., Vail, T.A., Rogers, G.T., Livingston, K.A., Whelan, J.G., Chin, M.K., Blanchard, C.M., Turgiss, J.L., Roberts, S.B. 2018. Effectiveness of an energy management training course on employee well-being: a randomized controlled trial. American Journal of Health Promotion.
Das, S., Karlsen, M.C., Blanchard, C., Roberts, S. 2018. Vegan diets. In: Apovian, C., Brouillard, L., Young, L., editors. Vegan Diet. Philadelphia, PA: Taylor & Francis Group. p. 99-112.
Deckersbach, T., Das, S., Urgan, L.E., Salindardi, T., Batra, P., Rodman, A.M., Arulpragasam, A.R., Dougherty, D., Roberts, S. 2014. Pilot randomized trial demonstrating reversal of obesity-related abnormalities in reward system responsivity to food cues with a behavioral intervention. Nutrition and Diabetes. 4:e129.