Wednesday, January 15, 2025
1/15/2025
Project Summary/Abstract Despite the widely-recognized importance and complexity of the post-burn hypermetabolic response, the underlying mechanisms by which a thermal injury induces and sustains hypermetabolism for years after the injury are essentially unknown. Recently, adipose tissue has been recognized as an essential player in the induction and persistence of hypermetabolism after burn injury. Like cold stress, burn injury induces the browning of white adipose tissue (WAT), in which subcutaneous WAT converts to a more brown-like adipose termed beige/brite adipose tissue (BAT). These otherwise quiescent beige cells adopt brown-like features, including multilocular lipid droplets and high UCP1 expression. Moreover, browning drives a conversion in mitochondrial function, uncoupling the respiratory chain from ATP synthesis and predominantly producing heat, thereby sending these already hypermetabolic patients into metabolic overdrive. While browning can have beneficial effects in patients with obesity and diabetes, we believe that browning in burn patients fuels high metabolic rates and alters plasma lipid profiles, leading to accelerated development and progression of cachexia, hyperglycemia, and organ steatosis thereby worsening outcomes of severely burned patients. The overarching hypothesis of this proposal is that browning of the adipose tissue is a central process in the pathologic hypermetabolic response, and one of the main mediators of persistent hypermetabolism after burn. This hypothesis will be systematically tested using a series of murine knock outs in our established burn model. The aim of this proposal is to study the mediators, function, consequences and potential treatments of the browning response after burn. The four specific aims (SA’s) are, firstly, to determine the consequences of browning on outcomes after burn (SA 1). Next, we will determine the metabolic and physiologic consequences of browning after burn (SA 2). We will proceed to determine central mediators by which a burn induces browning and hypermetabolism (SA 3) before proceeding to uncover whether therapeutic targeting of browning can improve outcomes after burn (SA 4). In summary, to date, the cellular and molecular mechanisms underlying the post-burn hypermetabolic response have not been identified, and despite improved clinical care, the detrimental sequelae of this response lead to a substantial post-burn morbidity and mortality. In this proposal we will explore the mechanism of induction of beige adipose post-burn, the signals leading from adipose to hypermetabolism, catabolism and dysfunction of various organs, and explore targeted disruptions in these cascades in order to develop specific therapeutics to improve outcomes. Our work will be carried out with a systematic series of murine knock-outs using a validated burn model. This project has value from a basic science standpoint and is highly relevant for patient outcomes.
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