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

2024 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
Obesity and Metabolism: A. When we generated mice with brown adipocyte specific deficiency of acyl CoA synthetase 4 (ACSL4) we did not observe a reduction in body fat or alterations in energy expenditure or alterations in brown adipocyte energetic gene expression or metabolism. As a result, it was no longer appropriate to pursue studies on isolated or cultured brown adipocytes nor on isolated mitochondria in brown fat. B. During the five years of study investigating ACSL4 expression in mice, we also investigated whether ACSL4 expression in immune (myeloid) cells protects against diet-induced obesity. The goal was to understand mechanisms that promote obesity in organisms fed a high caloric diet which is a worldwide epidemic. We were able to demonstrate that myeloid (immune) cell deficiency of ACSL4 protected against diet-induced obesity. Myeloid cell ACSL4 deficiency in mice fed a high caloric diet burned more calories. We are now investigating the underlying mechanisms why myeloid cell ACSL4 protected against diet-induced obesity. Importantly, developing dietary approaches to reducing ACSL4 expression in immune cells will likely ameliorate the development of diet-induced obesity and associated health complications. C. We also investigated the role of fat cell (adipocyte) interferon regulatory factor 8 (IRF8) in the development of diet-induced obesity. Similar to our studies on immune cell ACSL4, the goal of these studies was to elucidate the mechanisms that promote obesity in organisms fed a high caloric diet. We were able to demonstrate during the course of this project that reduced expression of the gene, interferon regulatory factor 8 (IRF8) in fat cells protected against the development of diet-induced obesity. In mice with fat cell deficiency of IRF8 fed a high calorie diet, the mice burned more calories. D. We are presently investigating the underlying mechanisms for the increased energy expenditure with reduced expression of IRF8. Developing dietary approaches to reducing IRF8 expression in fat cells will likely ameliorate the development of diet-induced obesity and associated health complications no longer able to demonstrate that adipocyte deficiency of ACSL4 protected against adiposity and increased energy expenditure. Energy Metabolism: A. In support of Objective 1, we evaluated whether self-selected diet composition predicts short-term (12 months) and long-term (24 months) adherence to calorie restriction. Using the Geometric Framework for Nutrition (GFN) methodology, we completed analyses of how self-selected dietary intake changes during calorie restriction. We reported that calorie restriction resulted in higher intake of protein and carbohydrates and lower intake of fat. More importantly, we showed that high protein intake combined with higher carbohydrate intake promoted greater adherence to calorie restriction. B. In support of Objective 2, we conducted weight loss interventions in military-, worksite-, and community-based settings. We found that weight loss interventions had benefits for on cardiometabolic health, weight-related health, and quality of life in very different populations including in military family members, employees of diverse worksites, and community-dwelling individuals. By demonstrating that weight loss programs using videoconferencing is just as effective as those using in-person counselling, we have identified potential strategies to expand the reach and inclusivity of much-needed interventions and intervention support. C. In support of Objective 3, we pilot-tested COCO (Conversational Calorie Counter) Nutritionist, a mobile application that uses natural spoken language to reduce the burden of food logging. COCO Nutritionist eliminates the need to log food and find suitable food codes — steps that are time-consuming and typically completed by participants or nutritionists. It accomplishes such food-logging by extracting the amounts and types of foods from natural language and automatically maps them to USDA food codes. In the first demonstration of this method, our pilot showed no significant difference in energy intake between values obtained by COCO Nutritionist and those obtained by multiple-pass, interviewer-administered 24-hour recall (a gold-standard method). D. In support of Objective 4, we have established a weight control registry with data from over 3,000 participants who have self-reported their weight, quality of life, and weight management lifestyle practices and behaviors. We have completed our 12- and 24-month follow-up of U.S. participants.

Accomplishments

Review Publications
Das, J.K., Banskota, N., Candia, J., Griswold, M.E., Orenduff, M., De Cabo, R., Corcoran, D.L., Das, S., De, S., Huffman, K.M., Kraus, V.B., Kraus, W.E., Martin, C.K., Racette, S.B., Redman, L.M., Schilling, B., Belsky, D.W., Ferrucci, L. 2023. Calorie restriction modulates the transcription of genes related to stress-response and longevity in human muscle: The CALERIE study. Aging Cell. https://doi.org/10.1111/acel.13963.
Aversa, Z., White, T.A., Heeren, A.A., Hulshizer, C.A., Saul, D., Zhang, X., Molina, A.J., Redman, L.M., Martin, C.K., Racette, S.B., Huffman, K.M., Bhapkar, M., Khosla, S., Das, S., Fielding, R.A., Atkinson, E.J., LeBrasseur, N.K. 2023. Calorie restriction reduces biomarkers of cellular senescence in humans. Aging Cell. https://doi.org/10.1111/acel.14038.
Das, S., Silver, R., Senior, A., Gilhooly, C.H., Bhapkar, M., Le Couteur, D. 2023. Diet composition, adherence to calorie restriction, and cardiometabolic disease risk modification. Aging Cell. https://doi.org/10.1111/acel.14018.
Mengjie, Y., Hu, F.B., Yanping, L., Cabral, H., Das, S., Deeney, J.T., Zhou, X., Paik, J.M., Moore, L.L. 2023. Types of dairy foods and risk of fragility fracture in the nurses' health study cohort. The American Journal of Clinical Nutrition. https://doi.org/10.1016/j.ajcnut.2023.09.015.
Waxiry, R., Ryan, C.P., Corcoran, D.L., Huffman, K.M., Kobor, M.S., Kothari, M., Graf, G.H., Kraus, V.B., Kraus, W.E., Lin, D.S., Pieper, C.F., Ramaker, M.E., Bhapkar, M., Das, S., Ferrucci, L., Hastings, W.J., Kebbe, M., Parker, D., Racette, S.B., Shaley, I., Schilling, B., Belsky, D.W. 2023. Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial. Nature Aging. https://doi.org/10.1038/s43587-022-00357-y.
Kim, R., Hashimoto, A., Markosyan, N., Tyurin, V.A., Tyurina, Y.Y., Kar, G., Fu, S., Segal, M., Gerique, L., Kossenkov, A., Gebregziabher, B.A., Tobias, J.W., Hicks, K., Halpin, R.A., Cvetesic, N., Deng, H., Donthireddy, L., Greenberg, A., Nam, B., Vonderheide, R.H., Nefedova, Y., Kagan, V.E., Gabrilovich, D. 2022. Ferroptosis of tumor neutrophils causes immune suppression in cancer. Nature. https://doi.org/10.1038/s41586-022-05443-0.
Bailey, R.L., Low Dog, T., Smith-Ryan, A., Das, S., Baker, F.C., Madek-Erdogan, Z., Hammond, B.R., Sesso, H.D., Eapen, A., Mitmesser, S.H., Wong, A., Nguyen, H. 2022. Sex differences across the life course: a focus on unique nutritional and health considerations among women. Journal of Nutrition. https://doi.org/10.1093/jn/nxac059.