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

• 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
• 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

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.

项目摘要 肥胖是一个重要的公共卫生问题，在成人和儿童中的流行率都在增加。肥胖 增加了许多共病疾病包括败血症和败血症相关并发症的风险。现在 肥胖与慢性全身性炎症状态有关，因为许多细胞 在脂肪组织内具有炎症性质。危重病与脂肪组织重塑有关 甚至在没有肥胖的情况下也会发生。有两种功能和组织学上不同类型的 脂肪组织：白色脂肪组织（WAT）和棕色脂肪组织（BAT）。WAT呈现BAT表型 响应于应激刺激（冷应激、烧伤），这一过程被称为布朗宁，其特征在于： 解偶联蛋白（UCP）-1的增加。在BAT中，UCP 1对产热作用很重要。布朗宁增加 能量消耗和氧气消耗，赋予防止肥胖和改善胰岛素敏感性的保护。 信号转导子和转录激活子3（STAT 3）是脓毒症中重要的急性期反应物， 也影响脂解作用，因此可能是布朗宁的重要调节剂。肥胖对脂肪组织的影响 对脓毒症引起的危重病的反应尚未得到很好的研究。我们实验室的数据表明， 脂肪组织布朗宁发生在多微生物败血症后的非肥胖小鼠中，但在肥胖小鼠中受损。 我们研究的长期目标是了解身体脂肪的机制，在正常情况下， 过量，有助于改变败血症引起的严重疾病的免疫反应。核心假设 我们的建议是，在脓毒症脂肪组织经历表型和功能的变化， 促进恢复，但这一过程在肥胖症中受损。我们计划验证我们的假设， 通过实现以下三个具体目标。在目标1中，我们将确定函数 脂肪组织在肥胖和非肥胖小鼠脓毒症期间恢复中的贡献。在目标2中， 确定STAT 3对肥胖和非肥胖患者的炎症和代谢反应的贡献， 小鼠败血症期间。在目标3中，我们将确定肥胖和非肥胖儿童的脂肪组织是否 在离体内毒素刺激期间经历与布朗宁一致的表型变化。的作用 脂肪组织在肥胖症和无肥胖症时都参与全身炎症反应 在危重病期间尚未探索，这是我们调查的重点。这一点很重要，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 受试者可以为患者带来改进的治疗。