Am J Physiol Endocrinol Metab. 2023 Jul 05.
High levels of plasma lactate are associated with increased mortality in critically injured patients, including those with severe burns. While lactate has long been considered a waste product of glycolysis, it was recently revealed that it acts as a potent inducer of white adipose tissue (WAT) browning, a response implicated in mediating post-burn cachexia, hepatic steatosis and sustained hypermetabolism. Despite the clinical presentation of hyperlactatemia and browning in burns, whether these two pathological responses are linked is currently unknown. Here, we report that elevated lactate plays a causal signaling role in mediating adverse outcomes after burn trauma by directly promoting WAT browning. Using WAT obtained from human burn patients and mouse models of thermal injury, we show that the induction of post-burn browning is positively correlated with a shift towards lactate import and metabolism. Furthermore, daily administration of L-lactate is sufficient to augment burn-induced mortality and weight loss in vivo. At the organ level, increased lactate transport amplified the thermogenic activation of WAT and its associated wasting, thereby driving post-burn hepatic lipotoxicity and dysfunction. Mechanistically, the thermogenic effects of lactate appeared to result from increased import through MCT transporters, which in turn increased intracellular redox pressure, [NADH/ NAD+], and expression of the batokine, FGF21. In fact, pharmacological inhibition of MCT-mediated lactate uptake attenuated browning and improved hepatic function in mice after injury. Collectively, our findings identify a signaling role for lactate that impacts multiple aspects of post-burn hypermetabolism, necessitating further investigation of this multifaceted metabolite in trauma and critical illness.
Keywords: Adipose; browning; burns; hypermetabolism; lactate