The role of T cells in adipose tissue inflammation and insulin resistance during weight cycling
The role of T cells in adipose tissue inflammation and insulin resistance during weight cycling
批准号:
10347316
负责人:
Matthew Alexander Cottam
金额:
$1.17万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-03-01 至 2022-06-30
关键词:
AcuteAdaptive Immune SystemAddressAdipocytesAdipose tissueAffectAgeAnimalsAntigensAutomobile DrivingBehaviorBody Weight decreasedCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCD8B1 geneCardiovascular DiseasesCell CountCell SurvivalCellsCharacteristicsClonalityClone CellsControl AnimalDevelopmentDiabetes MellitusExposure toFat-Restricted DietFatty acid glycerol estersFlow CytometryFunctional disorderGene Expression ProfileGenetic ModelsGenetic TranscriptionGlucoseGlucose ClampGlucose IntoleranceGoalsGoldHeartHomeostasisHumanImmuneImmune systemImpairmentInflammationInflammatoryInsulin ResistanceLinkLiteratureMembrane ProteinsMemoryMetabolicMetabolic DiseasesMetabolismModelingMonoclonal AntibodiesMusNon-Insulin-Dependent Diabetes MellitusNutrientNutritionalObesityOutcomePersonsPhenotypePlayPopulationPrevalenceProductionRecoveryReportingResolutionRiskRoleSocietiesSurfaceT cell clonalityT-Cell DepletionT-Cell ReceptorT-LymphocyteTissuesTumor-infiltrating immune cellsVisceralWeightWeight GainWorkadverse outcomebaseblood glucose regulationcardiovascular disorder riskcomorbiditycytokinedesigndiet-induced obesityexperienceexperimental studyglucose toleranceglucose uptakein vivo Modelinsightinsulin sensitivitymalemetabolic phenotypemouse modelnovelobesogenicprogrammed cell death protein 1responserestrainttherapeutic targetweight maintenance
中文摘要
项目摘要
平均而言,成功减肥的人将在5年内恢复80%的减肥效果。
体重减轻(WL)和体重恢复(WL),被称为“重量循环”(WC),与
增加人类罹患心血管疾病和2型糖尿病的风险。至
确定在以下人群中观察到的进行性代谢失调的原因和相关性
WC,我们开发了一种WC的小鼠模型,在该模型中,60%的高脂饮食和10%的低脂饮食交替进行
强烈地引发体重增加和体重增加的循环。相比之下,WC动物的葡萄糖耐量受损
以年龄、体重和肥胖相匹配的高脂肪喂养的对照组动物。全身性血糖变化
调节部分依赖于渗入新陈代谢组织的适应性免疫细胞,包括
脂肪组织(AT),在肥胖进展过程中。然而,这些重要细胞的表型
在WL和WC期间,还没有表征。基于新的初步发现CD8+T细胞
细胞在WL期间表现出免疫耐受标记,在WC期间表现出侵袭性炎症潜能,
我推测AT CD8+T细胞在WL期间暂时变得耐受,但很有能力
在WC后重新激活,是WC期间观察到的胰岛素敏感性受损所必需的。我们
在肥胖期间观察到内脏AT中T细胞受体多样性的丧失,表明T细胞
克隆扩增是对营养触发的抗原的反应。为了进一步阐明克隆的作用
T细胞的扩张可能在WL和WC小鼠的全身性葡萄糖处理中起作用,我将对T细胞进行表征
使用测序和基于流式细胞术的方法进行单细胞分辨。此外,我们还将
使用耗竭和遗传模型来阻止长寿的CD8+T细胞对血糖的贡献
在厕所期间观察到不耐受。经历过肥胖的CD8+T细胞将被单抗耗尽
WL之前的抗体。恢复后,动物将再次受到饮食诱导的肥胖的挑战
识别缺乏经验的CD8+T细胞是否无法促进AT的胰岛素抵抗特征
厕所。随之而来的是,CD70-/-小鼠无法长期维持激活的T细胞的存活,
WC和代谢表型以确定是否是长期驻留在AT中的CD8+T细胞
是推动全身性血糖失调所必需的。这两款车型的表型都是
金标高胰岛素正血糖钳暴露不同人群胰岛素敏感性差异
控制小鼠。最终,这项建议寻求填补新陈代谢和炎症方面未得到满足的需求
AT重塑过程中T细胞表型和功能的研究。因此,这样做的结果是
该项目将通过提供对T细胞驱动的机制的清楚洞察来影响后续工作
用于维持体重的炎症和治疗靶点。
英文摘要
Project Summary
On average, people who successfully lose weight will regain 80% of the lost weight within 5 years.
Bouts of weight loss (WL) and weight regain, referred to as “weight cycling” (WC), are associated with
increased risk of cardiovascular disease and of development of type 2 diabetes mellitus in humans. To
identify causes and correlation of the progressive metabolic dysregulation observed in humans who
WC, we have developed a mouse model of WC in which alternating 60% high and 10% low-fat diets
robustly induce cycles of weight gain and WL. Glucose tolerance in WC animals is impaired compared
to age, weight, and adiposity-matched high-fat fed control animals. Alterations in systemic glucose
regulation is partially dependent on adaptive immune cells that infiltrate metabolic tissues, including
adipose tissue (AT), during progression of obesity. However, the phenotype of these important cells
during WL and WC has not been characterized. Premised on novel preliminary findings that CD8+ T
cells display markers of immunotolerance during WL and aggressive inflammatory potential during WC,
I hypothesize that AT CD8+ T cells transiently become tolerant during WL, but are potently
reactivated after WC and are necessary for impaired insulin sensitivity observed during WC. We
have observed a loss of T cell receptor diversity in visceral AT during obesity, indicating that T cells
clonally expand in response to a nutritionally-triggered antigen. To further elucidate the role that clonal
T cell expansion may play in systemic glucose handling in WL and WC mice, I will characterize T cells
with single-cell resolution using sequencing and flow cytometry-based approaches. Additionally, we will
use depletion and genetic models to block long-lived CD8+ T cells from contributing to glucose
intolerance observed during WC. Obesity-experienced CD8+ T cells will be depleted using monoclonal
antibodies prior to WL. After recovery, animals will again be challenged with diet-induced obesity to
identify if inexperienced CD8+ T cells are unable to promote insulin resistance characteristic of AT after
WC. Concomitantly, CD70-/- mice, which fail to maintain survival of activated T cells long-term, will be
WC and metabolically phenotyped to determine whether it is long-lived AT-resident CD8+ T cells that
are necessary for driving systemic glucose dysregulation. Both of these models will be phenotyped with
gold-standard hyperinsulinemic euglycemic clamps to expose differences in insulin sensitivity from
control mice. Ultimately, this proposal seeks to fill an unmet need in the metabolism and inflammation
fields regarding T cell phenotype and function during AT remodeling. As a result, the outcomes of this
project will influence subsequent work by providing clear insight into mechanisms of T-cell driven
inflammation and therapeutic targets for weight maintenance.
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