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

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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.