Research Project: Energy Regulation and Obesity

Location: Jean Mayer Human Nutrition Research Center On Aging

2019 Annual Report

Objectives
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.

Approach
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: This is the final report for the project 8050-51000-097-00D. The goal of the Energy Metabolism lab is to conduct research that informs improvements in interventions to reduce obesity and related noncommunicable diseases, especially in older adults. The lab studies biological and behavioral determinants of weight regulation with a variety of methods and conducts short-term studies and randomized controlled trials of different types of interventions. This work is important for aging, because the consequences of excess body weight (for example diabetes and cardiovascular disease) disproportionally affect older adults. The Laboratory has had considerable productivity in this 5-year project with the following highlights. The lab has made significant progress toward advancing the field of worksite weight management with studies on the effects of incorporating a greater emphasis on control of hunger and food cravings into standard behavioral approaches to weight management. In a pilot randomized controlled trial in Objective 2 enrolling 133 adults from 4 worksites, there was 8% mean weight loss over 6 months and no significant weight regain at 12 months and a low drop-out rate of only 11%. As part of the pilot randomized controlled trial, the lab examined associations between weight change, hunger and food cravings. The lab demonstrated significant reductions in both hunger and food cravings compared to a wait-listed control and observed significant correlations between hunger and weight loss (R2=0.557, P<0.001) and between cravings and weight loss (R2=0.112, P<0.05). The lab also provided the first preliminary demonstration (N=13 randomized participants), suggesting that brain reward system can be changed so that participants learn to prefer healthy food more and like unhealthy food less. These accomplishments suggest substantial brain plasticity, giving hope that healthy foods can become more popular with the right kinds of public health strategies. The recently completed trials in Boston worksites and military dependents will extend this work and inform future scalability. Caloric restriction is the only intervention known to extend lifespan in animal models. In Objective 1, the lab's team has conducted a landmark 2-year randomized controlled trial of human caloric restriction examining potential benefits and negative effects across metabolic and psychological health parameters. Moreover, the program was successful in achieving 10% caloric restriction over 2 years--the first demonstration that this is possible. The Laboratory showed that caloric restriction has a range of benefits in adults without obesity consistent with the effects of caloric restriction on extending lifespan in animal models, including improvements in cardiometabolic risk factors and immune function. Furthermore, there were no negative effects (e.g. hunger, mood), and quality of life was not impaired. These results provide a remarkable demonstration of the potential population-wide benefits of caloric restriction. The fact that volunteers implemented the regimen on their own without adverse effects indicates that caloric restriction can now be considered for a role in public health. The next steps will be to explore predictors of relative success for sustainable weight loss and caloric restriction in order to understand how future programs can potentially be improved and implemented without loss of safety. The lab has explored the role of dietary composition on resting metabolic rate because identifying ways to boost resting metabolic rate during weight loss can support sustainable weight control. In Objective 3 the lab demonstrated for the first time that there is no effect of low versus high glycemic carbohydrates on metabolic rate but a significant benefit of whole grain versus refined grain carbohydrates. On average, there was an almost 100 kcal/day benefit from consuming whole grains because the whole grains caused increases in metabolic rate and fecal energy losses. These results address the ongoing scientific controversy over whether all calories are equal and provide strong evidence that whole grains have important benefits for weight management. The next initiative in this area will be to seek funding to broaden the range of nutrients examined. Understanding the underlying causes of overeating will help drive effective policy initiatives to support healthy weight regulation in older adults. In Objective 2, the lab has investigated the accuracy of stated calories in restaurants. The lab showed that quick-serve restaurants, contrary to speculation, do not provide more calories per meal than full-serve restaurants. Further, >90% of restaurants provide calories in excess of typical requirements for a single meal, with some providing more than a whole day’s worth of calories. Because humans do not easily compensate for overeating by undereating at another meal, excessive portions likely contribute to the obesity epidemic. In addition, the lab measured the energy content of popular meals in 5 international countries and found excess values comparable to in the U.S. in all countries except China, which had lower values. The results suggest that high restaurant meal energy contents are contributing to the global obesity epidemic. OBESITY AND METABOLISM LAB: This is the final report for the project 8050-51000-097-00D. During the five years of the project, experiments were performed to determine the relative role of perilipin 2 (plin2) and acyl CoA synthetase 5 (ACSL5) expression within hepatocytes and intestinal enterocytes in diet-induced obesity and associated metabolic complications. Researchers in the Obesity and Metabolism lab in Boston, Massachusetts demonstrated that deficiency of plin2 with intestinal enterocytes did not protect against diet-induced obesity or metabolic complications such as insulin resistance. Deficiency of plin2 within hepatocytes of mice significantly reduced the accumulation of liver triglycerides but did not protect against the development of diet-induced obesity or systemic insulin resistance. Furthermore, these studies demonstrated that hepatocyte deficiency of plin2 protected against increased accumulation of hepatocyte triglyceride by resulting in increased rates of autophagy and fat oxidation. In studies of mice with hepatocyte ACSL5 deficiency, researchers observed no protection against diet-induced obesity, hepatic steatosis, or insulin resistance. In contrast, mice with intestinal enterocyte deficiency of ACSL5 were robustly protected against the development of diet-induced obesity, and data indicate an improved metabolic profile. Their studies revealed that intestinal ACSL5 deficiency protected against diet-induced obesity because of reduced intake of a high fat, high sucrose diet-- likely due in part to increased serum levels of glucagon-like peptide-1 (GLP-1). Significantly, there are approved drugs for humans that increase GLP-1 for the treatment of diabetes and obesity. Thus, reductions in intestinal ACSL5 expression may provide a novel approach to increasing GLP-1 and ameliorating obesity and associate metabolic complications.

Accomplishments
1. ENERGY METABOLISM LAB: Glycemic index of carbohydrates has no effect on burning calories, but there is a benefit to eating whole grains. Obesity and overweight are epidemics in the United States. ARS-funded researchers in Boston, Massachusetts, explored the role of dietary composition on metabolism because identifying ways to burn calories can support sustainable weight control. Researchers demonstrated for the first time that there is no effect of low versus high glycemic carbohydrates on burning calories. However, there was a significant benefit of whole grain versus refined grain carbohydrates on the rate at which calories are burned. On average, whole grains caused participants to expend 100 extra calories per day. These results address the ongoing scientific controversy over whether all calories are equal and provide strong evidence that whole grains have important benefits for weight management. These results could lead to nutritional guidance that curbs the obesity epidemic in older adults, a population disproportionately affected by obesity.

2. OBESITY AND METABOLISM LAB: Absence of a specific protein protects against the development of fatty liver. Previous studies have demonstrated that the obesity-associated fatty liver predisposes individuals to the development of steatohepatitis, liver failure, and liver cancer. ARS-funded researchers in Boston, Massachusetts, demonstrated that genetically modified mice that do not express perilipin 2 within liver cells were significantly protected against the development of fatty liver. The ARS-funded researchers furthermore demonstrated that reductions in the expression of perilipin 2 resulted in increased rates of fat breakdown and fat burning. The discovery that reducing the expression of liver perilipin 2 reduces accumulation of fat within the liver may help scientists develop new ways to treat obesity-associated fatty liver.

Review Publications
Dao, C.M., Sokolovska, N., Brazeilles, R., Affeldt, S., Pelloux, V., Prifti, E., Chilloux, J., Verger, E.O., Kayser, B., Aron-Wisnewsky, J., Ichou, F., Pujos-Guillot, E., Hoyles, L., Juste, C., Dore, J., Dumas, M., Rizkalla, S.W., Holmes, B.A., Zucker, J., Clement, K. 2019. A data integration multi-omics approach to study calorie restriction-induced changes in insulin sensitivity. Frontiers in Physiology. 9:1958. https://doi.org/10.3389/fphys.2018.01958.
Roberts, S., Das, S., Suen, V.M., Pihlajamaki, J., Kuriyan, R., Steiner-Asiedu, M., Taetzsch, A.G., Anderson, A.K., Silver, R.E., Barger, K., Krauss, A.J., Karhunen, L., Zhang, X., Hambly, C., Schwab, U., Melo, A.T., Fassini, P.G., Taylor, S.F., Economos, C., Kurpad, A.V., Speakman, J.R. 2018. Measured energy content of frequently purchased restaurant meals: multi-country cross sectional study. British Medical Journal. 363:k4864. https://doi.org/10.1136/bmj.k4864.
Taetzsch, A.G., Das Sai, K., Brown, C., Krauss, A., Silver, R.E., Roberts, S. 2018. Are gluten-free diets more nutritious? An evaluation of self-selected and recommended gluten-free and gluten-containing dietary patterns. Nutrients. 10(12). https://doi.org/10.3390/nu10121881.
Dao, M.C., Subar, A.F., Warthon-Medina, M., Cade, J.E., Burrows, T., Golley, R.K., Forouhi, N.G., Pearce, M., Homes, B.A. 2018. Dietary assessment toolkits: an overview. Public Health Nutrition. https://doi.org/10.1017/S1368980018002951.
Il'yasova, D., Fontana, L., Bhapkar, M., Pieper, C.F., Spasojevic, I., Redman, L.M., Das, S., Huffman, K.M., Kraus, W.E. 2018. Effects of 2 years of caloric restriction on oxidative status assessed by urinary F2-isoprostanes: the CALERIE 2 randomized clinical trial. Aging Cell. 17(2):e12719. https://doi.org/10.1111/acel.12719.
Lean, M.E., Astrup, A., Roberts, S. 2018. Making progress on the global crisis of obesity and weight management. British Medical Journal. 361:k2538. https://doi.org/10.1136/bmj.k2538.
Das, S., Balasubramanian, P., Weerasekera, Y.K. 2017. Nutrition modulation of human aging: the calorie restriction paradigm. Molecular and Cellular Endocrinology. 455:148-157. https://doi.org/10.1016/j.mce.2017.04.011.
Dao, C.M., Clement, K. 2017. Gut microbiota and obesity: concepts relevant to clinical care. European Journal of Internal Medicine. 48:18-24. https://doi.org/10.1016/j.ejim.2017.10.005.
Kraus, W.E., Bhapkar, M., Huffman, K.M., Pieper, C.F., Das, S., Redman, L.M., Villareal, D.T., Rochon, J., Roberts, S., Ravussin, E., Holloszy, J.O., Fontana, L. 2019. 2 years of calorie restriction and cardiometabolic risk (CALERIE): exploratory outcomes of a multicentre, phase 2, randomised controlled trial. Lancet Diabetes Endocrinology. https://doi.org/10.1016/S2213-8587(19)30151-2.
Dao, C., Belda, E., Prifti, E., Everard, A., Kayser, B., Bouillot, J., Chevallier, J., Pons, N., Le Chatelier, E., Ehrlich, D., Dore, J., Aron-Wisnewsky, J., Zucker, J., Cani, P.D., Clement, K. 2019. Akkermansia muciniphila abundance is lower in severe obesity but its increased level after bariatric surgery is not associated with metabolic health improvement. American Journal of Clinical Nutrition. https://doi.org/10.1152/ajpendo.00140.2019.
Takemoto, M., Manini, T.M., Rosenberg, D.E., Lazar, A., Zlatar, Z.Z., Das, S., Kerr, J. 2018. Diet and activity assessments and interventions using technology in older adults. American Journal of Preventive Medicine. 55(4):e105-e115. https://doi.org/10.1016/j.amepre.2018.06.005.
McCrory, M.A., Harbaugh, A.G., Appeadu, S., Roberts, S.B. 2019. Fast-food offerings in the United States in 1986, 1991, and 2016 show large increases in food variety, portion size, dietary energy, and selected micronutrients. Journal of the Academy of Nutrition and Dietetics. 119(6):923-933. https://doi.org/10.1016/j.jand.2018.12.004.
McClung, H.L., Ptomey, L.T., Shook, R.P., Aggarwal, A., Gorczyca, A.M., Sazonov, E.S., Becofsky, K., Weiss, R., Das, S. 2018. Dietary intake and physical activity assessment: current tools, techniques, and technologies for use in adult population. American Journal of Preventive Medicine. 55(4):e93-e104. https://doi.org/10.1016/j.amepre.2018.06.011.
Dao, M.C., Messer, E., Conigliaro, T., Sakaida, K., Ouellette, A.F., Himaras, V., Thiron, S., Roberts, S.B. 2019. Different and unequal: a qualitative evaluation of salient factors influencing energy intake in adults with overweight and obesity. Nutrients. 11(6). https://doi.org/10.3390/nu11061365.