Impact of the Adipose Tissue Microenvironment on Atherosclerosis

脂肪组织微环境对动脉粥样硬化的影响

• 批准号: 10063545
• 负责人: Willa A Hsueh
• 金额: $ 51.09万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-15 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10063545
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Antigen Presentation; Antioxidants; Aorta; Apolipoprotein E; Atherosclerosis; Attenuated; Blocking Antibodies; Blood Vessels; Body Weight; Body fat; Bone Marrow; Bone Marrow Transplantation; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cardiovascular Diseases; Cardiovascular system; Cells; Cholesterol; Communication; Coronary artery; Data; Development; Diabetes Mellitus; Diet; Disease; Dyslipidemias; Fc Receptor; Gene Expression; Goals; Guidelines; Harvest; High Fat Diet; Histocompatibility Antigens Class II; Homeostasis; Hyperlipidemia; Hypertension; Immune; Immunotherapeutic agent; Immunotherapy; Inflammation; Inflammatory; Ingestion; Insulin; Insulin Resistance; Interferons; Investigation; Knock-in; Knock-out; Leptin; Lesion; Lipids; Low Density Lipoprotein Receptor; Mediating; Meta-Analysis; Metabolic; Metabolic syndrome; Metabolism; Modality; Modeling; Mus; Mutation; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Paper; Pathogenesis; Peripheral; Phenotype; Plasma; Population; Production; Regulatory T-Lymphocyte; Risk; Risk Factors; Signal Transduction; Site; T-Lymphocyte; Testing; Th1 Cells; Thinness; Transgenes; Transplantation; Triglycerides; Visceral; Weight; Wild Type Mouse; adaptive immunity; base; blood glucose regulation; cardiovascular disorder risk; combat; endothelial dysfunction; excessive weight gain; improved; insight; insulin sensitivity; knock-down; laser capture microdissection; macrophage; middle age; molecular phenotype; novel; novel strategies; obese person; overexpression; preservation; protein expression; receptor; systemic inflammatory response; trafficking; tumor-immune system interactions

ABSTRACT Changes in the abundance and phenotypes of adipose tissue immune cells are a major determinant of systemic inflammation and insulin resistance during excess weight gain. Adipocyte expression of the class II major histocompatibility complex (MHCII) occurs early during high-fat diet (HFD) challenge and parallels pro- inflammatory changes in MHCII-activated CD4+ adipose resident T cells (ARTs) implicating the adipocyte as an instigator of obesity-induced inflammation. Adipocyte-specific MHCII null (aMHCII-/-) mice created to test this hypothesis 1) developed substantially less visceral adipose tissue (VAT) inflammation than their wild-type (WT) littermates when challenged with HFD, despite identical changes in body weight and %body fat, 2) had markedly more VAT regulatory T cells (Tregs), but not in other peripheral sites; 3) were more insulin sensitive with better glucose homeostasis and 4) when bred into an atherosclerosis prone LDLR-/- background, attenuated accelerated atherosclerosis without affecting plasma cholesterol and triglyceride levels. Tregs are a major component of the CD4+ ART population in lean mice, where they suppress inflammation to maintain normal VAT metabolism, but dramatically decrease during HFD-challenge. However, VAT Tregs are preserved in HFD-fed aMHCII-/- mice, which likely explains the improved metabolic and cardiovascular phenotype in these mice. The aMHCII-/- mutation, thus, provides a unique opportunity to specifically alter adipose inflammation, independent of obesity, dyslipidemia, and changes in peripheral T cells to investigate its impact on obesity- induced complications, particularly atherosclerosis. We hypothesize that decreased adipose inflammation attenuates atherosclerosis even in the presence of obesity. Specific Aims will address: 1) the effect of A) aMHCII-deficiency and B) visceral adipose tissue (VAT)-specific Treg depletion (via cells with defective VAT Treg homeostasis or an IL-33 receptor blocking antibody which inhibits IL-33-induced VAT Treg proliferation) on diet-induced atherosclerosis; 2) whether A) constitutive, adipocyte-specific MHCII overexpression promotes adipose inflammation to enhance atherosclerosis, and B) administration of IL-33 attenuates atherosclerosis through a VAT Treg-dependent mechanism; and 3) changes in the immune cell composition and molecular phenotypes in aortic lesions in mice with and without aMHCII mutations using T cell flow analyses of aorta, laser capture microdissection of plaque macrophages, and investigation of macrophage trafficking from VAT to aorta. The results of this investigation using adipocyte MHCII knock-in/knock-out models and several novel approaches to specifically alter VAT, but not peripheral, Tregs will determine the contributions of adipose tissue inflammation and VAT Tregs to the pathogenesis of obesity-associated atherosclerosis. This mechanistic insight sets the stage for development of better immune-based therapeutic strategies to combat CVD in the setting of obesity.

摘要

项目成果

Association of Serum Aldosterone and Plasma Renin Activity With Ambulatory Blood Pressure in African Americans: The Jackson Heart Study.

• DOI: 10.1161/circulationaha.120.050896
• 发表时间: 2021-06-15
• 期刊: Circulation
• 影响因子: 37.8
• 作者: Joseph JJ;Pohlman NK;Zhao S;Kline D;Brock G;Echouffo-Tcheugui JB;Sims M;Effoe VS;Wu WC;Kalyani RR;Wand GS;Kluwe B;Hsueh WA;Abdalla M;Shimbo D;Golden SH
• 通讯作者: Golden SH

Adipocytes, Innate Immunity and Obesity: A Mini-Review.

脂肪细胞、先天免疫和肥胖：小型回顾。

• DOI: 10.3389/fimmu.2021.650768
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Blaszczak AM;Jalilvand A;Hsueh WA
• 通讯作者: Hsueh WA

Adipocyte DIO2 Expression Increases in Human Obesity but Is Not Related to Systemic Insulin Sensitivity.

• DOI: 10.1155/2018/2464652
• 发表时间: 2018
• 期刊: Journal of diabetes research
• 影响因子: 4.3
• 作者: Bradley D;Liu J;Blaszczak A;Wright V;Jalilvand A;Needleman B;Noria S;Renton D;Hsueh W
• 通讯作者: Hsueh W

Obesogenic Memory Maintains Adipose Tissue Inflammation and Insulin Resistance.

• DOI: 10.20900/immunometab20200023
• 发表时间: 2020-01-01
• 期刊: Immunometabolism
• 作者: Blaszczak, Alecia M;Bernier, Matt;Hsueh, Willa A
• 通讯作者: Hsueh, Willa A

Association of Adiposity With Incident Diabetes Among Black Adults in the Jackson Heart Study.

• DOI: 10.1161/jaha.120.020716
• 发表时间: 2021-09-21
• 期刊: Journal of the American Heart Association
• 影响因子: 5.4
• 作者: Joseph JJ;Kluwe B;Echouffo-Tcheugui JB;Zhao S;Brock G;Kline D;Odei JB;Kalyani RR;Bradley DP;Hsueh WA;Sims M;Golden SH
• 通讯作者: Golden SH