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

2022 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. In support of Objective 1, we evaluated whether self-selected diet composition predicts short-term (12-month) and long-term (24-month) adherence to calorie restriction (CR). Using the Geometric Framework for Nutrition (GFN) methodology, we completed analyses of how self-selected dietary intake changes during CR. In addition, we quantified the percentage of energy consumed from protein, carbohydrates, and fat for participants randomized to a CR intervention compared to an ad libitum intake control condition. We assessed how these data inform short-term (12-month) and long-term (24-month) adherence to a CR regimen. Our results indicate that the average self-selected composition of the diet changes significantly over a short- and long-term CR regimen, whereas no such change is observed in the control group. In particular, the CR group consumed a diet higher in protein and lower in fat over time. Additional evidence suggests 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. A manuscript is in preparation and will be submitted to the Journal of Gerontology. In support of Objective 3, we published a study that pilot-tested COCO Nutritionist, a new app. COCO Nutritionist is slated to be the first tool of its kind to use natural spoken language to reduce the burden of food logging by eliminating the need to log food and find suitable food codes — steps that have been previously conducted by participants or their nutritionists. From natural spoken language, the app extracts the amounts and types of foods and automatically maps them to USDA food codes. In our pilot test, there was no significant difference in energy intake between values obtained with the new method and gold standard values obtained by multiple-pass 24-hour dietary recall. Since food logging is a central component of nationally recommended programs for weight management, this work represents an important advance and will be extended to all segments of the population in future research conducted by our group. In support of Objective 4, we collaborated with scientists in Kuwait, Greece, and Italy to enroll participants in the International Weight Control Registry (IWCR). The value of these data lies in their unique contribution to understanding the different ways in which weight can be successfully managed. By including participants from outside the United States, we broadened the types of dietary and behavioral practices that can be identified as associated with healthy weight loss maintenance. This discovery science approach can inform future interventions to support weight loss maintenance in U.S. adults, something that is urgently needed given the lack of sustainable success in current interventions. Obesity and Metabolism. We have made progress on our previously proposed studies on the role of adipocyte IRF8 in the development of diet induced obesity in mice. Initiation of these studies was delayed due to the pandemic. We have now demonstrated that mice with deficiency of adipocyte IRF8 are protected against diet-induced obesity while having increased systemic energy expenditure. The increased energy expenditure is likely due in part or all to activation of brown adipose tissue. Using superficial infrared imaging, we demonstrated increased heat production in the back of the mouse consistent with increased activation of brown adipocytes.

Accomplishments
1. Energy Metabolism. New approach to weight loss successfully tested in military families. Traditional weight loss interventions are based on consumption of low-calorie diets, exercise, and self-monitoring food intake and activity. ARS-funded researchers in Boston, Massachusetts, conducted a randomized trial with 238 adults who were overweight or obese and dependents of active-duty or retired military personnel. The researchers tested a method of weight loss based on a new theoretical model incorporating biological considerations in weight management. The new method focused on consumption of high-satiety foods and did not require daily completion of food logs, which is the most burdensome component of traditional interventions. Participants focused on managing hunger through diets high in fiber and protein and the use of set menus and recipes that provided more structure. This intervention was as successful as the traditional Diabetes Prevention Program based on a low-calorie diet and monitoring of food intake. This new method may be a more practical option for people seeking to lose weight, therefore providing people with another approach to weight loss.

2. Obesity and Metabolism. Decreased expression of a specific gene can increase hormones that ameliorate diseases. Adiponectin is a hormone produced by fat cells that improves the regulation of glucose, reduces hepatic fat accumulation, and protects against the development of heart disease. In obese mice and humans, fat cell production of adiponectin is reduced. ARS funded researchers in Boston, Massachusetts, have demonstrated that obesity increases the expression of the gene and protein called interferon-related factor 8 in adipocytes. Mice were generated with deficiency of interferon-related factor 8 and when fed a high caloric diet to induce adiposity, the reduction in expression of interferon-related factor 8 resulted in increased expression of adiponectin. Based upon these studies, researchers can develop diets that reduce fat cell expression of interferon related 8 and thus increase fat cell expression of adiponectin which would contribute to healthy aging.

Review Publications
Anton, S., Das, S., Mclaren, C., Roberts, S. 2021. Application of social cognitive theory in weight management: Time for a biological component?. Obesity. 29(12):1982-1986. https://doi.org/10.1002/oby.23257.
Taylor, S., Korpusik, M., Das, S., Gilhooly, C., Simpson, R., Glass, J., Roberts, S. 2021. Use of natural spoken language with automated mapping of self-reported food intake to food composition data for low-burden real-time dietary assessment: method comparison study. Journal of Medical Internet Research. 23(12):e26988. https://doi.org/10.2196/26988.
Reeves, A., Sansbury, B.E., Pan, M., Han, X., Spite, M., Greenberg, A. 2021. Myeloid-specific deficiency of long-chain acyl CoA synthetase 4 reduces inflammation by remodeling phospholipids and reducing production of arachidonic acid-derived proinflammatory lipid mediators. Journal of Immunology. 207(11): 2744-2753. https://doi.org/10.4049/jimmunol.2100393.
Speakman, J.R., Yamada, Y., Sagayama, H., Berman, E.S., Ainslie, P.N., Andersen, L.F., Anderson, L.J., Arab, L., Baddou, I., Bedu-Addo, K., Blaak, E.E., Blanc, S., Bonomi, A.G., Bouten, C.V., Bovet, P., Buchowski, M.S., Butte, N.F., Camps, S.G., Close, G.L., Cooper, J., Creasy, S.A., Das, S., Cooper, R., Dugas, L., Ebbelings, C.E., Ekelund, U., Entringer, S., Forrester, T., Fudge, B.W., Goris, A.H., Gurven, M., Hambly, C., El Hamdouchi, A., Hoos, M.B., Hu, S., Joonas, N., Joosen, A.M., Katzmarzyk, P., Kempen, K.P., Kimura, M., Kraus, W.E., Kushner, R., Lambert, E.V., Leonard, W.R., Lessan, N., Ludwig, D.S., Martin, C., Medin, A.C., Meijer, E.P., Morehen, J.C., Morton, J.P., Neuhouser, M., Nicklas, T., Ojiambo, R.M., Person, M., Pietilainen, K.H., Pitsiladis, Y.P., Plange-Rhule, J., Plasqui, G., Prentice, R., Rabinovich, R.A., Racette, S.B., Raichlen, D.A., Ravussin, E., Reynolds, R., Roberts, S.B., Schuit, A.J., Sjodin, A.M., Stice, E., Urlacher, S.S., Valenti, G., Van Etten, L.M., Van Mil, E.A., Wells, J.C., Wilson, G., Wood, B.M., Yanovski, J., Yoshida, T., Zhang, X., Murphy-Alford, A.J., Loechl, C., Melanson, E.L., Luke, A.H., Pontzer, H., Rood, J., Schoeller, D.A., Westerterp, K.R., Wong, W.W. 2021. A standard calculation methodology for human doubly labeled water studies. Cell Reports Medicine. 2(2):100203. https://doi.org/10.1016/j.xcrm.2021.100203.
Mishra, A., Liu, S., Promes, J., Harata, M., Sivitz, W.I., Finck, B., Bhardwaj, G., O'Neill, B., Kang, C., Sah, R., Strack, S., Stephens, S., King, T., Jackson, L., Greenberg, A., Anokey-Danso, F., Ahima, R.S., Ankrum, J., Lami, Y. 2021. Perilipin 2 downregulation in Beta cells impairs insulin secretion under nutritional stress and damages mitochondria. Journal of Clinical Investigation Insight. 6(9):e144341. https://doi.org/10.1172/jci.insight.144341.
Westerterp, K.R., Yamada, Y., Sagayama, H., Ainslie, P.N., Andersen, L.F., Anderson, L.J., Arab, L., Baddou, I., Bedu-Addo, K., Blaak, E.E., Blanc, S., Bonomi, A.G., Bouten, C.V., Bovet, P., Buchowski, M.D., Butte, N.F., Camps, S.G., Close, G., Cooper, J., Das, S., Cooper, R., Dugas, L., Ekelund, U., Entringer, S., Forrester, T., Fudge, B.W., Goris, A.H., Gurven, M., Hambly, C., El Hamdouchi, A., Hoos, M.B., Hu, S., Joonas, N., Joosen, A.M., Katzmarzyk, P., Kempen, K.P., Kimura, M., Kraus, W.E., Kushner, R., Lambert, E.V., Leonard, W.R., Lessan, N., Martin, C.K., Medin, A.C., Meijer, E.P., Morehen, J.C., Morton, J.P., Neuhouser, M., Nickles, T.A., Ojiambo, R.M., Pietilainen, K.H., Pitsiladis, Y.P., Plange-Rhule, J., Plasqui, G., Prentice, R., Rabinovich, R.A., Racette, S.B., Raichlen, D.A., Ravussin, E., Reynolds, R., Roberts, S., Schuit, A.J., Sjodin, A.M., Stice, E., Urlacher, S.S., Valenti, G., Van Etten, L.M., Van Mil, E.A., Wells, J.C., Wilson, G., Wood, B.M., Yanovski, J., Yoshida, T., Zhang, X., Murphy-Alford, A.J., Loechl, C., Luke, A.M., Rood, J., Schoeller, D.A., Pontzer, H., Wong, W.W., Speakman, J.R. 2021. Physical activity and fat-free mass during growth and in later life. American Journal of Clinical Nutrition. https://doi.org/10.1093/ajcn/nqab260.
Zhang, Y., Song, M., Chan, A.T., Schernhammer, E.S., Wolpin, B.M., Stampfer, M.J., Meyerhardt, J.A., Fuchs, C.S., Roberts, S., Willett, W.C., Hu, F.B., Giovannucci, E.L., Ng, K. 2021. Unrestrained eating behavior and risk of digestive system cancers: a prospective cohort study. American Journal of Clinical Nutrition. 14(5):1612-162. https://doi.org/10.1093/ajcn/nqab235.
Dorling, J.L., Van Vliet, S., Huffman, K.M., Kraus, W.E., Bhapkar, M., Pieper, C.F., Stewart, T., Das, S., Racette, S.B., Roberts, S.B., Ravussin, E., Redman, L.M., Martin, C.K. 2020. Effects of caloric restriction on human physiological, psychological, and behavioral outcomes: highlights from CALERIE phase 2. Nutrition Reviews. 79(1):98-113. https://doi.org/10.1093/nutrit/nuaa085.
Careau, V., Halsey, L.G., Pontzer, H., Ainslie, P.N., Andersen, L.F., Anderson, L.J., Arab, L., Baddou, I., Bedu-Addo, K., Blaak, E.E., Blanc, S., Bonomi, A.G., Bouten, C.V., Buchowski, M.S., Butte, N.F., Camps, S.G., Close, G.L., Cooper, J., Das, S., Cooper, R., Dugas, L., Eaton, S.D., Ekelund, U., Entringer, S., Forrester, T., Fudge, B.W., Goris, A.H., Gurven, M., Hambly, C., El Hamdouchi, A., Hoos, M.B., Hu, S., Joonas, N., Joosen, A.M., Katzmarzyk, P., Kempen, K.P., Kimura, M., Kraus, W.E., Kushner, R., Lambert, E.V., Leonard, W.B., Lessan, N., Martin, C.K., Medin, A.C., Meijer, E.P., Morehen, J.C., Morton, J.P., Neuhouser, M., Nicklas, T., Ojjambo, R.M., Pietilainen, K.H., Pitsiladis, Y.P., Plange-Rhule, J., Plasque, G., Prentice, R., Rabinovich, R.A., Racette, S.B., Raichlen, D.A., Ravussin, E., Reilly, J.J., Reynolds, R., Roberts, S., Schuit, A.J., Sjodin, A.M., Stoce, E., Urlacher, S.S., Valenti, G., Van Etten, L.M., Van Mil, E.A., Wells, J.C., Wilson, G., Wood, B.M., Yanovski, J., Yoshida, T., Zhang, X., Murphy-Alford, A.J., Loechl, C., Luke, A.M., Rood, J., Sagayama, H., Schoeller, D.A., Wong, W.W., Yamada, Y., Speakman, J.R. 2021. Energy compensation and adiposiy in humans. Current Biology. https://doi.org/10.1016/j.cub.2021.08.016.
Rimbach, R., Yamada, Y., Sagayama, H., Ainslie, P.N., Andersen, L.F., Anderson, L.J., Arab, L., Baddou, I., Bedu-Addo, K., Blaak, E.E., Blanc, S., Bonomi, A.G., Bouten, C.V., Bovet, P., Buchowski, M.S., Butte, N.F., Camps, S.G., Close, G.L., Cooper, J., Das, S., Dugas, L.L., Ekelund, U., Entringer, S., Forrester, T., Fudge, B.W., Goris, A.H., Gurven, M., Hambly, C., El Hamdouchi, A., Hoos, M.B., Hu, S., Joonas, N., Joosen, A.M., Katzmarzyk, P., Kempen, K.P., Kimura, M., Kraus, W.E., Kushner, R., Lambert, E.V., Leonard, W.R., Lessan, N., Martin, C.K., Medin, A.C., Meijer, E.P., Morehen, J.C., Morton, J.P., Neuhouser, M.L., Nicklas, T., Ojiambo, R.M., Pietilainen, K.H., Pitsiladis, Y.P., Plange-Rhule, J., Plasqui, G., Prentice, R., Rabinovich, R.A., Racette, S.B., Raichlen, D.A., Ravussin, E., Reynolds, R., Roberts, S., Schuit, A.J., Sjodin, A.M., Stice, E., Urlacher, S.S., Valenti, G., Van Etten, L.M., Van Mil, E.A., Wells, J.C., Wilson, G., Wood, B., Yanovski, J., Yoshida, T., Zhang, X., Murphy-Alford, A.J., Loechl, C., Luke, A.H., Rood, J., Schoeller, D.A., Westerterp, K.R., Wong, W.W., Speakman, J.R., Pontzer, H. 2022. Total energy expenditure is repeatable in adults but not associated with short-term changes in body composition. Nature Communications. 13(1):99. https://doi.org/10.1038/s41467-021-27246-z.
Das, S., Bukhari, A., Taetzsch, A.G., Ernst, A.K., Rogers, G., Gilhooly, C., Hatch-McChesney, A., Blanchard, C.M., Livingston, K.A., Silver, R., Martin, E., McGraw, S.M., Chin, M.K., Vail, T.A., Lutz, L.J., Montain, S.J., Pittas, A.G., Lichtenstein, A.H., Allison, D.B., Dickinson, S., Chen, X., Saltzman, E., Young, A.J., Roberts, S. 2021. Randomized trial of a novel lifestyle intervention compared with the Diabetes Prevention Program for weight loss in adult dependents of military service members. American Journal of Clinical Nutrition. 114(4):1546-1559. https://doi.org/10.1093/ajcn/nqab259.
Das, S., Miki, A., Blanchard, C.M., Sazanov, E.S., Gilhooly, C., Dey, S., Wolk, C.B., Khoo, C.H., Hill, J.O., Shook, R. 2021. Perspective: Opportunities and challenges of technology tools in dietary and activity assessment: Bridging stakeholder viewpoints. Advances in Nutrition. https://doi.org/10.1093/advances/nmab103.
Pernar, C.H., Chomistek, A.K., Barnett, J.B., Ivey, K., Al-Shaar, L., Roberts, S., Rood, J., Fielding, R.A., Block, J., Li, R., Willett, W.C., Parmigiani, G., Giovannucci, E.L., Mucci, L.A., Rimm, E.B. 2022. Validity and relative validity of alternative methods to assess physical activity in epidemiologic studies: Findings from the Men's Lifestyle Validation Study. American Journal of Epidemiology. https://doi.org/10.1093/aje/kwac051.
Fassini, P.G., Das, S., Suen, V.M., Magerowski, G., Marchini, J., Araujo da Silva Jr, W., Changyu, S., Alonso-Alonso, M. 2019. Appetite effects of prefrontal stimulation depend on COMT Val158Met polymorphism: a randomized clinical trial. Appetite. https://doi.org/10.1016/j.appet.2019.05.015.
Pontzer, H., Yamada, Y., Sagayama, H., Ainslie, P.N., Andersen, L.F., Anderson, L.J., Arab, L., Baddou, I., Bedu-Addo, K., Blaak, E.E., Blanc, S., Bonomi, A.G., Bouten, C.V., Bovet, P., Buchowski, M.S., Butte, N.F., Camps, S.G., Close, G.L., Cooper, J.A., Cooper, R., Das, S., Dugas, L.R., Ekelund, U., Entringer, S., Forrester, T., Fudge, B.W., Gories, A.H., Gurven, M., Hambly, C., El Hamdouchi, A., Hoos, M.B., Hu, S., Joonas, N., Joosen, A.M., Katzmarzyk, P., Kempen, K.P., Kimura, M., Kraus, W.E., Kushner, R.E., Lambert, E.V., Leonard, W.R., Lessan, N., Martin, C., Medin, A.C., Meijer, E.P., Morehen, J.C., Morton, J.P., Neuhouser, M.J., Nicklas, T.A., Ojiambo, R.M., Pietilainen, K.H., Pitsiladis, Y.P., Plange-Rhule, J., Plasqui, G., Prentice, R.L., Rabinovich, R.A., Racette, S.B., Raichlen, D.A., Ravussin, E., Reynolds, R.M., Roberts, S., Schuit, A.J., Sjodin, A.M., Stice, E., Urlacher, S.S., Valenti, G., Van Etten, L.M., Van Mil, E.A., Wells, J.C., Wilson, G., Wood, B.M., Yanovski, J., Yoshida, T., Zhang, X., Murphy-Alford, A.J., Loechl, C., Luke, A.H., Rood, J., Schoeller, D.A., Westerterp, K.R., Wong, W.W., Speakman, J.R. 2021. Daily energy expenditure through the human life course. Science. 373(6556):808-812. https://doi.org/10.1126/science.abe5017.
Dorling, J.L., Das, S., Racette, S.B., Apolzan, J.W., Zhang, D., Pieper, C.F., Martin, C.K. 2020. Changes in body weight, adherence, and appetite during 2 years of calorie restriction: the CALERIE 2 randomized clinical trial . European Journal of Clinical Nutrition. 74:1210-1220. https://doi.org/10.1038/s41430-020-0593-8.