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

2021 Annual Report

Objectives
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.

Approach
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, which fall variously under NP107; 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 1, a detailed statistical analysis plan was completed. Analyses of self-selected dietary intake changes during calorie restriction were also completed. The percentage of energy consumed from protein, carbohydrate, and fat for participants randomized to a calorie restriction intervention compared to an ad libitum intake control group were evaluated using the Geometric Framework for Nutrition, a novel statistical approach. We assessed how these dietary data inform short (12-month) and long-term (24-month) adherence to a calorie restriction regimen. An abstract outlining the preliminary results was presented in a symposium at the Gerontological Society of America in November 2020. Preliminary analyses of dietary composition during calorie restriction and cardiometabolic outcomes are complete. Final analyses are underway, and manuscript preparation is planned for the end of 2021. For Objective 3, we completed our new natural spoken language app analysis for self-reported dietary intake. A 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 smartphone the foods they consumed. We found no significant difference in daily energy intake between values obtained with the app and data obtained by the “gold-standard” multiple-pass 24h recall, and the paper is now at the revision stage in the Journal of Medical Internet Research. For Objective 4 we have worked with collaborators at the University of Alabama, the University of Colorado, the University of Kentucky, the Pennington Biomedical Institute, and West Point to improve our website to collect comprehensive data on dietary, physical activity, psychological and environmental factors related to healthy weight management. We have received Institutional Review Board (IRB) permission to use the website (Tufts is the IRB of record for all U.S. sites) and have enrolled > 2,000 U.S. participants. We now have 17 international sites at various stages of applying to their IRBs for permission to collaborate on the project. A manuscript describing the approach is in preparation and will be submitted for publication shortly. Obesity and Metabolism: We have now demonstrated that in obese mice, adipocyte expression of interferon related 8 (IRF8) reduces the expression of uncoupling protein 1 (UCP1) and sarco/endoplasmic reticulum Ca2+-ATPase 2b (SERCA2b). UCP1 and SERCA2b are two proteins that increase adipose tissue metabolism of fat and systemic metabolic rate. Adipocyte deficiency of IRF8 in obese female mice results in increased expression levels of UCP1 and SERCA2b, increased systemic energy expenditure, and protection against diet-induced obesity. We have extended those studies to demonstrate that adipocyte deficiency of IRF8 in male mice also protects against diet-induced obesity.

Accomplishments
1. ENERGY METABOLISM: Healthy nutrition and weight management can support healthy aging. Americans now spend an average of 10 years at the end of life in a state of disability, increasing from 5 years in the 1960s. ARS-funded researchers in Boston, Massachusetts, performed a comprehensive literature review and found strong evidence that healthy dietary patterns and maintenance of a healthy weight in the years leading to old age are associated with broad prevention of archetypal diseases and impairments associated with aging including noncommunicable diseases, sarcopenia, cognitive decline and dementia, osteoporosis, age-related macular degeneration, diabetic retinopathy, hearing loss, obstructive sleep apnea, urinary incontinence, and constipation. In addition, the published review found that randomized clinical trials have shown that disease-specific nutrition interventions can slow the progression—and in some cases effectively treat many established aging-associated conditions. In contrast to this strong scientific evidence for the vital roles of nutrition and weight management in healthy aging, middle-aged and older adults living in the U.S. typically consume diets with inadequate servings of healthy food groups and essential nutrients, along with an abundance of energy-dense but nutrient-weak foods that contribute to obesity. These findings emphasize that healthy nutrition has a broad, under-recognized role in preventing aging-related diseases and conditions and indicate that updated public health recommendations on nutrition are needed to support healthy aging.

2. OBESITY AND METABOLISM: Deficiency of a specific protein in fat cells results in increased metabolic rate and protects against the development of diet-induced obesity. Why certain people are more at risk for obesity remains unknown. ARS-funded researchers in Boston, Massachusetts, have demonstrated that a specific protein in fat cells found in mice increased metabolism and protected against diet-induced obesity. The significance of these findings is that in future studies, the investigators can develop specific diets that reduce the expression of this protein in fat cells of humans to protect against diet-induced obesity or ameliorate obesity. This discovery may result in devising nutritional approaches that will promote healthy weight and increase the health span of older adults.

Review Publications
Dao, C.M., Thiron, S., Messer, E., Sergeant, C., Sevigne, A., Huart, C., Rossi, M., Silverman, I., Sakaida, K., Bel Lassen, P., Sarrat, C., Arciniegas, L., Das, S., Gausseres, N., Clement, K., Roberts, S. 2020. Cultural influences on the regulation of energy intake and obesity: A qualitative study comparing food customs and attitudes to eating in adults from France and the United States. Nutrients. https://doi.org/10.3390/nu13010063.
Roberts, S., Silver, R., Das, S., Fielding, R.A., Gilhooly, C., Jacques, P.F., Kelly, J.M., Mason, J.B., McKeown, N.M., Rearson, M., Rowan, S., Saltzman, E., Shukitt-Hale, B., Smith, C.E., Taylor, A., Wu, D., Zhang, F., Panetta, K., Booth, S.L. 2021. Healthy aging: Nutrition matters, start early and screen often. Advances in Nutrition. https://doi.org/10.1093/advances/nmab032.
Berthoud, H., Seeley, R.J., Roberts, S. 2021. Physiology of Energy Intake in the Weight-Reduced State. Obesity. 29(S1):S25-S30. https://doi.org/10.1002/oby.23080.
Blanchard, C.M., Chin, M., Gilhooly, C., Barger, K., Matuszek, G.H., Miki, A., Cote, R.G., Eldridge, A.L., Green, H., Mainardi, F., Mehers, D., Ronga, F., Steullet, V., Das, S. 2021. Evaluation of PIQNIQ, a novel mobile application for capturing dietary intake. Journal of Nutrition. 151(5):1347-1356. https://doi.org/10.1093/jn/nxab012.
Griffin, J., Bejarano-Fernandez, E., Wang, X., Greenberg, A.S. 2021. Integrated action of autophagy and adipose tissue triglyceride lipase ameliorates diet-induced hepatic steatosis in liver specific PLIN2 knockout mice. Cells. 10(5):1016. https://doi.org/10.3390/cells10051016.
Dorling, J.L., Ravussin, E., Redman, L.M., Bhapkar, M., Huffman, K.M., Racette, S.B., Das, S.W., Apolzan, J.W., Kraus, W.E., Hochsmann, C., Martin, C.K. 2020. Effect of 2 years of calorie restriction on liver biomarkers: results from the CALERIE phase 2 randomized controlled trial. European Journal of Nutrition. https://doi.org/10.1007/s00394-020-02361-7.
Wishart, A., Conner, S., Guarin, J., Fatherree, J., Pang, Y., McGinn, R., Crews, R., Naber, S., Hunter, M., Greenberg, A.S., Oudin, M.J. 2020. Decellularized extracellular matrix scaffolds identify full-length collagen VI as a driver of breast cancer cell invasion in obesity and metastasis. Science Advances. https://doi.org/10.1126/sciadv.abc3175.
Greenberg, A., Reeves, A. 2021. The good and bad of adipose tissue macrophage exosomes in obesity. Cell Metabolism. 33(4):700-702. https://doi.org/10.1016/j.cmet.2021.03.011.