Macrophage inflammasome activation and the mechanism of lipolysis resistance in aged adipose

老年脂肪巨噬细胞炎症小体激活及抗脂解机制

• 批准号: 10012936
• 负责人: Christina Camell
• 金额: $ 24.61万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10012936
• 关键词: Activin Receptor; Adipocytes; Adipose tissue; Age; Aging; Automobile Driving; Body Temperature; Body mass index; CASP1 gene; Catecholamines; Cells; Chronic Disease; Data; Defect; Diet; Elderly; Extracellular Matrix; Extracellular Matrix Proteins; Failure; Family; Fatty Acids; Fibrosis; Flow Cytometry; Functional disorder; Gene Expression; Generations; Genes; Glycerol; Goals; Homeostasis; Human; Hydrolysis; In Vitro; Inflammaging; Inflammasome; Inflammation; Inflammatory; Insulin Resistance; Interleukin-1 beta; Lead; Ligation; Lipids; Lipolysis; Lipopolysaccharides; Messenger RNA; Metabolic Diseases; Mus; Nonesterified Fatty Acids; Obesity; Outcome; Pathway interactions; Process; Production; Regulation; Research; Resistance; Risk; Role; Signal Transduction; Starvation; Stress; Testing; Tissues; Transforming Growth Factor beta; Transgenic Mice; Triglycerides; Visceral; aged; base; career; design; end of life; exercise capacity; experimental study; growth differentiation factor 3; healthspan; improved; macrophage; marenostrin; member; mouse model; novel; receptor; response; senescence; therapeutic target; transcriptome sequencing

Project Summary Visceral adiposity is increased in the elderly, despite a normal body-mass-index, and this increase is associated with increased risk for metabolic diseases. Lipolysis is the first step in the generation of free fatty acids and glycerol as energy substrates, is reduced with age and may be responsible for the increased adiposity in the elderly. The changes that drive reduced lipolysis are unclear, but understanding those changes may provide ways to restore lipolysis and reduce visceral adiposity in the elderly. Adipose macrophages are tissue resident cells that are critical in maintaining tissue homeostasis. During aging they have elevated levels of inflammasome activation and control lipolysis reduction. Senescence and fibrosis are also increased with aging, but whether they contribute to reduced lipolysis is unclear. We have identified macrophage-expressed growth differentiation factor (GDF)-3, a member of the TGFβ family, as a negative regulator of adipose lipolysis and potential trigger of inflammation, senescence and fibrosis in aging. The overall goal of this study is to identify the role for macrophage-expressed GDF3 in promoting inflammation, senescence and fibrosis to drive lipolysis resistance in the aged adipose tissue. Specifically, we propose to (1) determine how GDF3 increases NLRP3 inflammasome activation and lipolysis resistance, (2) characterize senescent macrophages and the determine whether GDF3 drives senescence in adipose macrophages and (3) identify whether GDF3 is required for ECM production and increased fibrosis in aged adipose. In Aim 1, we will identify activin receptors and whether SMAD signaling alters inflammasome activation in macrophages in vitro. We will extend these in vitro results and examine whether GDF3 is required for age-induced lipolysis resistance and inflammation using aged mouse models of Gdf3-deficiency. In Aim 2, we will define senescent macrophages using a unique transgenic mouse model permitting the identification of senescent cells using flow cytometry. To test for a requirement of GDF3, we will delete GDF3 in the transgenic mice to analyze adipose macrophages using flow cytometry and gene expression. Aim 3 will identify extracellular matrix proteins that are produced by macrophages in response to GDF3. Additionally, Gdf3+/+ and Gdf3-/- mouse models of aging and RNA sequencing will be used to identify novel candidates regulating GDF3 in adipose fibrosis. Completion of this project will permit identification of the role for GDF3 in age-induced lipolysis resistance and as a potential therapeutic target in treatment of inflammation and lipolysis resistance for humans during aging. The long term goals of the candidate are to obtain an independent academic career with research focused on understanding the mechanisms driving adipose dysfunction in aging.

项目总结