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ARS Home » Northeast Area » Boston, Massachusetts » Jean Mayer Human Nutrition Research Center On Aging » Research » Research Project #436678

Research Project: Energy Met.: Novel Approaches to Facilitating Successful Energy Regulation in Aging--Obesity & Met.: Role of Adipocyte Metabolism in the Development of Obesity and Associated Metabolic Complications

Location: Jean Mayer Human Nutrition Research Center On Aging

2020 Annual Report

Energy Metabolism: Objective 1: Determine nutritional factors, including meal patterns and novel dietary composition factors (e.g., types of dietary fiber and salt), that influence adherence to calorie restriction regimens to improve weight regulation and reduce metabolic aging. Sub-objective 1A: Identify significant dietary and biobehavioral predictors of weight, body fat change, and adherence to a calorie restriction regimen. Sub-objective 1B: Determine the effects of changing from a typical (high) to a recommended (low) level of dietary sodium on energy regulation in adults. Objective 2: Evaluate the effectiveness, sustainability, and acceptability of different approaches to weight control and prevention of obesity in diverse adult population groups. Objective 3: Develop new methodology for improving the accuracy and precision of assessment of energy and nutrient intake in adults. Objective 4: Identify positive and negative influences of specific food culture parameters, including attitudes to healthy food and external pressures to overeat, on energy regulation and risk of obesity in different population groups. Obesity and Metabolism: Objective 1: To determine the relative role and mechanisms by which ACSL4 expression in white and brown adipocytes modulates adipocyte oxygen consumption, systemic energy expenditure and the development of diet-induced obesity and associated metabolic complications. Sub-objective 1A: To determine how adipocyte ACSL4 expression in response to a high fat diet (HFD) compromises white adipose tissue function and whole-body systemic metabolism Sub-objective 1B: To determine whether ACSL4, 4-hydroxy-trans-2, 3-nonenal (4-HNE) and/or mitochondrial-derived reactive oxygen species (ROS) play compulsory roles in mediating diet-induced perturbations in gWAT, adipocyte mitochondrial function and cellular bioenergetics Sub-objective 1C: To determine the role of ACSL4 in promoting HFD-induced brown adipocyte dysfunction and DIO Objective 2: To determine the role and mechanisms by which interferon related factor 8 (IRF8) adipocyte expression is regulated in diet-induced obesity and modulates the development of diet-induced obesity and associated metabolic complications.

Energy Metabolism: The mission of the Energy Metabolism Laboratory is to understand the effects of lifestyle factors and dietary composition on energy metabolism and weight regulation, and extend our research to underserved and global populations. 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 while continuing to advance the science of nutrition and energy regulation. Studies in our laboratory include in-depth biological examinations of the impact of different dietary factors on energy regulation and body composition, development of new approaches to tracking dietary intake, and randomized controlled trials testing practical interventions that can be scaled for population-wide benefits in different population groups. Obesity and Metabolism: Excessive dietary intake of nutrients above the body’s energetic needs results in obesity and associated metabolic complications. Adipocyte dysfunction, which occurs with increased storage of triacylglycerol in adipocytes, is important in the development of diet-induced obesity (DIO) and associated metabolic complications. Obesity-associated adipocyte dysfunction is associated with features of premature aging such as p53 activation and increased adipose tissue inflammation. In this project plan, we propose to use mouse models to determine the role of specific proteins within adipocytes in the development of obesity and/or associated metabolic complications. Within cells, acyl-CoA synthetases (ACSL) converts fatty acids to fatty acid acyl CoA. Each of the five known ACSL isoforms has been hypothesized to direct acyl-CoAs to specific metabolic fates; we want to determine the role of acyl CoA synthetase 4 (ACSL4) in obesity-associated adipocyte metabolism. In a preliminary study, we investigated and observed that mice with adipocyte deficiency of ACSL4 are protected against DIO, p53 activation, and exhibit increased systemic energy expenditure (EE). In Objective 1 of our project plan we propose to determine the underlying DIO associated mechanisms by which ACSL4 modulates adipocyte and systemic EE and associated metabolic and inflammatory complications. In separate preliminary studies we have discovered that deficiency of interferon related factor 8 (IRF8), specifically within adipocytes of mice, protects against the development of DIO-associated hepatic steatosis and reduced fasting blood glucose. The goals of Objective 2 of this proposal is to elucidate the mechanisms by which adipocyte expression of IRF8 is regulated and the role of adipocyte IRF8 in DIO-associated detrimental alterations in adipose tissue such as adipose tissue inflammation and systemic metabolism.

Progress Report
ENERGY METABOLISM: Progress was made on all planned objectives for this year, all of which fall variously under NP107, C4, PS 4B] Component 3 (improving the scientific basis for updating national dietary standards and guidelines) and Component 4 (prevention of obesity and obesity-related diseases). For Objective 1A, we obtained a National Institute on Aging funded grant titled “Self-selected diet composition, adherence to caloric restriction, and cardiometabolic disease risk”. Using a novel analysis methodology, the Geometric Framework for Nutrition (GFN), we completed the preliminary analyses of how self-selected dietary intake, in particular, percentage energy consumed from protein, carbohydrate, and fat changes for participants randomized to a Calorie Restriction (CR) intervention compared to ad libitum intake. We assessed how these data inform short- (12-month) and long-term (24-month) adherence to a CR regimen. The preliminary results suggest that the average self-selected composition of the diet changes significantly over a short- and over the long-term CR regimen, whereas no such change was observed in the control group. In particular, the CR group consumed a diet higher in protein and lower in fat over time. There is additional evidence to suggest an effect of diet composition on adherence to a CR regimen. At 24 months, participants with the highest consumption of protein in the CR group tended to exhibit the highest level of adherence to the CR regimen. No such effect was observed during short-term CR. This analysis will be refined to ensure all covariates outlined in the proposal are accounted for. The associations of dietary fiber and glycemic load with CR adherence will also be evaluated. Using the GFN, we have also completed preliminary analyses of the dietary predictors of cardiometabolic responses to short- and long-term CR. The association between macronutrient composition and cardiometabolic risk factors were evaluated. The following outcomes were assessed: blood pressure, cholesterol (total, high-density lipoprotein [HDL], low-density lipoprotein [LDL], total cholesterol to HDL ratio), triglycerides, inflammatory markers (C-reactive protein, interleukin [IL]-6, IL-8, IL-B), insulin, glucose and using the more comprehensive indicator of cardio-metabolic response – the metabolic syndrome risk score. Preliminary analyses show no indication that dietary composition had an effect on cardiometabolic risk factors or the metabolic syndrome score over the short- and long-term CR. These analysis will be refined and will include evaluation of diet pattern scores and cardiometabolic risk factor changes. For Objective 3, we completed enrollment in a test of a new natural spoken language app for self-monitoring dietary intake. This collaboration with the Natural Spoken Language Group at the Massachusetts Institute of Technology developed an app that allows individuals to speak in natural language or type into a text box of a smart phone the foods they consumed. The app extracts data on the type of food and quantity and maps that to a food code and summarizes data across meals and days. In a preliminary analysis of the new app there is no significant difference in daily energy intake between values obtained with the app and data obtained by the “gold-standard” multiple pass 24h recall. For Objective 4, we have worked with our collaborators at the University of Alabama and University of Colorado to develop a website to collect comprehensive data on dietary, physical activity, psychological and environmental factors related to healthy weight management. We have received IRB permission to use the website and are in the process of creating a reliance agreement with our U.S. collaborators for Tufts to be the IRB of record for all work relating to this initiative. The 10 international sites are at various stages of applying to their own IRBs for permission to collaborate on the project. We anticipate this will become a substantial web-based activity that will allow for big data analyses on the broad range of factors associated with weight management success. OBESITY AND METABOLISM: We fed both male and female mice with adipocyte specific deficiency of interferon regulated 8 (IRF8) and mice that express IRF8 in adipocytes a high-caloric, high-fat diet (HFD). Interestingly, we observed that female mice with adipocyte specific deficiency of IRF8 when fed the high-fat diet were protected against the development of diet-induced obesity (DIO). After being on a 60% high fat, high carbohydrate diet for ten weeks, female mice which expressed IRF8 in adipocytes gained on average 9.8 + 1.6 grams of body fat mass per mouse while female mice with adipocyte IRF8 deficiency gained on average 4.2 + 2.4 grams of body fat mass per mouse However male mice with adipocyte specific deficiency of IRF8 when fed a HFD were not protected against the development of DIO.

1. ENERGY METABOLISM: Video-conferencing proves useful for diabetes prevention. Diabetes is a leading cause of death in the United States and is expected to continue increasing. ARS-funded researchers in Boston, Massachusetts, developed a videoconference-delivered version of the National Diabetes Prevention Program, a weekly program delivered in person by community-based trainers who teach participants how to make lasting lifestyle changes such as eating healthier, increasing physical activity and improving coping skills. The videoconferencing approach demonstrated it is just as effective as the original version delivered in person. The weekly video conferencing option is a significant advancement, especially in the current environment in which COVID-19 has restricted movement of people. This modified training approach will promote greater healthy weight management and prevention of type 2 diabetes without the need for burdensome and, at times challenging to attend in-person group meetings.

2. OBESITY AND METABOLISM: Fat cells lacking specific proteins protect female – but not male – mice from obesity. Obesity is increasing at alarming rates and contributes to the development of diabetes, liver disease, and cancer. ARS-funded researchers in Boston, Massachusetts, developed mice with reduced levels of protein in specific fat cells. Fat female mice that lacked the protein did not become obese when fed a high caloric diet. This result will provide valuable information in developing approaches to prevent diet-induced obesity.

Review Publications
Dorling, J.L., Bhapkar, M., Das, S., Racette, S.B., Apolzan, J.W., Fearnbach, S., Myers, C.A., Stewart, T.M., Martin, C.K. 2019. Changes in self-efficacy, eating behaviors and food cravings during two years of calorie restriction in humans without obesity. Appetite. 143.
Das, S., Mason, S.T., Vail, T.A., Blanchard, C.M., Chin, M.K., Rogers, G., Livingston, K.A., Turgiss, J.L. 2020. Sustained long-term effectiveness of an energy management training course on employee vitality and purpose in life. American Journal of Health Promotion. 34(2):177-188.
Taetzsch, A., Roberts, S.B., Gilhooly, C.H., Lichtenstein, A.H., Krauss, A.J., Bukhari, A., Martin, E., Hatch-McChesney, A., Das, S. 2020. Food cravings: associations with dietary intake and metabolic health. Appetite. 152.
Wang, W., Hao, X., Han, L., Yan, Z., Shen, W., Dong, D., Hasbargen, K., Bittner, S., Cortez, J., Greenberg, A.S., Azhar, S., Kraemer, F.B. 2019. Tissue-specific ablation of ACSL4 results in disturbed steroidogenesis. Endocrinology. 160(11):2517-2528.