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

PROJECT SUMMARY/ABSTRACT Sepsis is a leading cause of death in critically ill children and survivors of sepsis can have long-term problems. Obesity is a significant health problem but there is a benefit of obesity during critical illness, termed the obesity paradox. The mechanisms leading to the obesity paradox remain unknown. There are classically two functionally and histologically distinct types of adipose tissue: white adipose tissue (WAT) and brown adipose tissue (BAT). But a third type called beige adipocytes, also known as brown-in-white (brite) adipocytes, develop in response to various stimuli through a process known as WAT browning. Browning increases energy expenditure and oxygen consumption and may be detrimental during critical illness. The effect of obesity on the adipose tissue response to sepsis-induced critical illness has not been well explored in patients. Data from our laboratory demonstrates sepsis induces WAT browning and the sepsis-induced WAT browning is associated with increased inflammation and angiogenesis in non-obese but not obese mice. What is not known is whether adipose tissue remodeling occurs in children with sepsis and the impact of obesity. Based on these important data we are now able to translate these findings from murine sepsis to human sepsis. The long-term goal of our studies is to understand the mechanisms through which body fat, in normal and in excess, contributes to adipose tissue remodeling and affects outcomes in critically ill patients with sepsis. The central hypothesis of our proposal is sepsis-induced inflammation leads to adipose tissue alterations that impair recovery in non-obese patients. We plan to test our hypothesis and accomplish the objectives by completing the following three specific aims. In Aim 1 we will determine changes in body composition in critically ill children with sepsis. Patients will undergo noninvasive tracking of body composition with InBody Body Water Analyzer on admission and serially during their PICU course. In Aim 2 we will determine the mechanisms by which IL6 and STAT3 affect adipose tissue browning and the impact of obesity using ex vivo adipose spheroid sepsis models. In Aim 3 we will determine the role of angiogenesis and the impact of obesity using ex vivo adipose spheroid sepsis models. Aims 2 and 3 will utilize human adipose tissue obtained from obese and non- obese children undergoing abdominal surgery. We will identify the effect of sepsis on body fat in critically ill children and the mechanisms of adipose tissue remodeling. These findings may provide insight for future treatment strategies for critically ill patients.