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 肥胖是一个重大的公共卫生问题，成人和儿童的患病率提高。肥胖 增加了包括败血症在内的许多合并症和与败血症有关的并发症（包括败血症）的风险。现在 很好地确定肥胖与慢性全身炎症状态有关，因为许多细胞 在脂肪组织中具有炎症特性。危害疾病与脂肪组织重塑有关 即使没有肥胖症，也会发生。有两种功能和组织学不同类型的 脂肪组织：白色脂肪组织（WAT）和棕色脂肪组织（BAT）。 WAT采用蝙蝠表型 响应压力刺激（冷应激，烧伤损伤），这是一种称为褐变的过程，其特征是 解耦蛋白（UCP）-1的增加。在BAT中，UCP1对于热生成很重要。褐变增加 能源消耗和氧气消耗，赋予肥胖免受保护并提高胰岛素敏感性。 信号换能器和转录激活因子（STAT3）是败血症中重要的急性相反应物 还会影响脂解，因此可能是褐变的重要调节剂。肥胖对脂肪组织的影响 对败血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 脂肪组织褐变发生在多脂肪型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在正常和中的机制 过量，导致败血症引起的危重疾病的免疫反应改变。中心假设 我们的建议是，在败血症期间，脂肪组织经历表型和功能性变化， 促进恢复，但肥胖症会受到损害。我们计划检验我们的假设并完成 通过完成以下三个特定目标来实现目标。在AIM 1中，我们将确定功能 肥胖和非肥胖小鼠败血症期间脂肪组织在恢复过程中的贡献。在目标2中，我们将 确定STAT3对肥胖和非肥胖的炎症和代谢反应的贡献 败血症中的小鼠。在AIM 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，经历与褐变一致的表型变化。角色 脂肪组织有助于肥胖症中的全身性炎症反应，并且在没有肥胖症的情况下 在重症疾病期间尚未探索，这是我们调查的重点。这很重要，因为 了解可能影响肥胖和非肥胖的脂肪组织中发生的机械变化 受试者可以改善患者的治疗方法。