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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

Project Number: 8050-51000-105-000-D
Project Type: In-House Appropriated

Start Date: May 22, 2019
End Date: Mar 11, 2024

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.