Role of STAT3 in sepsis-induced adipose tissue browning and the impact of obesity

STAT3 在脓毒症诱导的脂肪组织褐变中的作用以及肥胖的影响

基本信息

批准号：
9454613
负责人：
Jennifer Melissa Kaplan
金额：
$ 31.8万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-25 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9454613
关键词：
Acute-Phase Proteins Acute-Phase Reaction Adipose tissue Adrenergic Agents Adult Affect Biological Body fat Brown Fat Burn injury Cells Child Chronic Comorbidity Critical Illness Data Disease Endotoxins Energy Metabolism Functional disorder Genetic Goals Health Histologic Hospitalization Human Immune response Impairment Inflammation Inflammatory Inflammatory Response Injury Intensive Care Units Interleukin-6 Investigation Knockout Mice Knowledge Laboratories Laboratory Study Lead Ligation Link Lipolysis Mediator of activation protein Metabolic Mitochondria Mus Non obese Obese Mice Obesity Operative Surgical Procedures Organ Outcome Oxygen Consumption Patients Pharmacology Phenotype Plasma Prevalence Process Property Proteins Public Health Puncture procedure Recovery Risk Role STAT protein Sepsis Stat3 protein Stimulus Stress TNF gene Testing Thermogenesis Tissue Differentiation Tissues density improved in vivo Model insight insulin sensitivity loss of function mortality negative affect obesity in children response septic targeted treatment uncoupling protein 1

项目摘要

Project Summary Obesity is a significant public health problem with an increasing prevalence in both adults and children. Obesity increases the risk for many comorbid disorders including sepsis and for sepsis-related complications. It is now well established that obesity is associated with a state of chronic systemic inflammation because many cells within adipose tissue have inflammatory properties. Critical illness is associated with adipose tissue remodeling and occurs even in the absence of obesity. There are two functionally and histologically different types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). WAT takes on a BAT phenotype in response to stressful stimuli (cold stress, burn injury), a process known as browning, and is characterized by an increase in uncoupling protein (UCP)-1. In BAT UCP1 is important for thermogenesis. Browning increases energy expenditure and oxygen consumption, confers protection from obesity and improves insulin sensitivity. Signal transducer and activator of transcription (STAT3) is an important acute phase reactant in sepsis that also affects lipolysis so may be an important regulator of browning. The effect of obesity on the adipose tissue response to sepsis-induced critical illness has not been well explored. Data from our laboratory suggest that adipose tissue browning occurs in non-obese mice after polymicrobial sepsis but is impaired in obese mice. The long-term goal of our studies is to understand the mechanisms through which body fat, in normal and in excess, contributes to the altered immune response in sepsis-induced critical illness. The central hypothesis of our proposal is that during sepsis adipose tissue undergoes phenotypical and functional changes that facilitates recovery but this process is impaired in obesity. We plan to test our hypothesis and accomplish the objectives by completing the following three specific aims. In Aim 1 we will determine the functional contribution of adipose tissue in recovery during sepsis in obese and non-obese mice. In Aim 2 we will determine the contribution of STAT3 to the inflammatory and metabolic responses in obese and non-obese mice during sepsis. In Aim 3 we will determine whether adipose tissue from obese and non-obese children undergoes phenotypic changes consistent with browning during ex vivo endotoxin stimulation. The role that adipose tissue contributes to the systemic inflammatory response in obesity and in the absence of obesity during critical illness has not been explored and is the focus of our investigations. This is significant because understanding the mechanistic changes that occur in adipose tissue that can affect obese and non-obese subjects can lead to improved therapies for patients.

项目概要肥胖是一个重大的公共卫生问题，在成人和儿童中的患病率日益增加。肥胖增加许多合并症的风险，包括脓毒症和脓毒症相关并发症。现在是众所周知，肥胖与慢性全身炎症状态有关，因为许多细胞脂肪组织内具有炎症特性。危重疾病与脂肪组织重塑有关即使没有肥胖也会发生。有两种功能和组织学上不同的类型脂肪组织：白色脂肪组织（WAT）和棕色脂肪组织（BAT）。 WAT 具有 BAT 表型对压力刺激（冷应激、烧伤）的反应，这一过程称为褐变，其特征是解偶联蛋白（UCP）-1 的增加。在 BAT 中，UCP1 对于生热作用很重要。褐变增加能量消耗和氧气消耗，防止肥胖并提高胰岛素敏感性。信号转导子和转录激活子 (STAT3) 是脓毒症中重要的急性期反应物，也影响脂肪分解，因此可能是褐变的重要调节剂。肥胖对脂肪组织的影响对脓毒症引起的危重疾病的反应尚未得到很好的探索。我们实验室的数据表明多种微生物败血症后，非肥胖小鼠的脂肪组织会发生褐变，但肥胖小鼠的脂肪组织会受损。我们研究的长期目标是了解正常和正常情况下身体脂肪的机制。过量，会导致败血症引起的危重疾病中免疫反应的改变。中心假设我们的建议是，在脓毒症期间，脂肪组织经历表型和功能变化，促进恢复，但这一过程在肥胖症中会受到损害。我们计划检验我们的假设并实现通过完成以下三个具体目标来实现目标。在目标 1 中，我们将确定函数脂肪组织对肥胖和非肥胖小鼠败血症期间恢复的贡献。在目标 2 中，我们将确定 STAT3 对肥胖和非肥胖炎症和代谢反应的贡献败血症期间的小鼠。在目标 3 中，我们将确定脂肪组织是否来自肥胖和非肥胖儿童在离体内毒素刺激期间经历与褐变一致的表型变化。所扮演的角色脂肪组织有助于肥胖和不肥胖的全身炎症反应危重症期间的情况尚未探讨，是我们调查的重点。这很重要，因为了解脂肪组织中发生的可能影响肥胖和非肥胖的机制变化受试者可以改善患者的治疗方法。