Burn Induces Browning of the Subcutaneous White Adipose Tissue in Mice and Humans

Abstract

SUMMARY Burn is accompanied by long-lasting immunometabolic alterations referred to as hypermetabolism that are characterized by a considerable increase in resting energy expenditure and substantial whole-body catabolism. In burned patients, the length and magnitude of the hypermetabolic state is the highest of all patients and associated with profoundly increased morbidity and mortality. Unfortunately, the mechanisms involved in hypermetabolism are essentially unknown. We hypothesized that the adipose tissue plays a central role for the induction and persistence of hypermetabolism post-burn injury. Here, we show that burn induces a switch in the phenotype of the subcutaneous fat from white to beige, with associated characteristics such as increased mitochondrial mass and UCP1 expression. Our results further demonstrate the significant role of catecholamines and interleukin-6 in this process. We conclude that subcutaneous fat remodeling and browning represent an underlying mechanism that explains the elevated energy expenditure in burn-induced hypermetabolism.

Mechanisms of metabolic dysfunction in cancer-associated cachexia

“…Notably, browning is not restricted to one experimental model and is not associated with one specific cancer type, since it was documented in complementary model systems, including genetically engineered mouse models (GEMMs), carcinogen-induced cancers, syngeneic transplants of murine cancer cells, and xenogeneic transplants of human cancer tissue (Petruzzelli et al 2014). Recently, browning of WAT has been shown to take part in the pathogenesis of hypermetabolism commonly observed in other morbid conditions, like post-burn injury, severe adrenergic stress, and kidney failure (Kir et al 2015;Patsouris et al 2015;Sidossis et al 2015). Treatment of mice with a synthetic thyroid hormone receptor agonist induces adaptive thermogenesis in subcutaneous WAT, thus suggesting a role for WAT browning also in hyperthyroidism (Lin et al 2015).…”

Therapeutic Approaches to Combatting Hypermetabolism in Severe Burn Injuries

“…We detected that adipocytes in the fat collected from burned patients during their last surgery were enriched in mitochondria. We then showed that there is a significant positive correlation between IL-6 and measured resting energy expenditure in burned patients [40]. Therefore, subcutaneous fat remodeling and browning illustrates an underlying mechanism that helps explain the elevated energy expenditure observed in burn-induced hypermetabolism.…”

“…Furthermore, the elderly population is a vulnerable group that requires a multi-modal approach to improve the outcomes since they display a hypermetabolic response which differs from that of adult burn patients. Early excision and closure of the burn wound post burn injury is extremely important in alleviating the hypermetabolic response and improving mortality and morbidity [4,6,40]. Nutrition is crucial in supplying the energy supply required for wound recovery, and for the attenuation of hypermetabolism and protein catabolism.…”

“…Early excision and closure of the wound post burn injury is the most significant single treatment to alleviate the hypermetabolic response as the institution of this practice in burn care considerably attenuates the hypermetabolic response [6] and improves the mortality rates [4,40]. Excision and closure of burn wounds surpassing 50% TBSA within the first three days of injury resulted in a 40% decrease in the resting energy expenditure in comparison with patients with similar burns whose wounds were excised and closed one week after injury [6].…”

The biochemical alterations underlying post-burn hypermetabolism

“…It is also likely that catecholamines activate transcription factors such as CREB and c-Fos, leading to the induction of MAPK family consisting of ERK1/2, JNK1/2/3 and p38, therefore prolonging the hyperinflammatory response following a severe burn [29], [30] and [31]. Furthermore, it has been shown that, similar to IL-6, catecholamines can induce browning of inguinal WAT, thus increasing the rate of lipolysis [32]. As is the case with inflammatory cytokines, the surge in catecholamines is thought to play a crucial role in orchestrating the initial stress response, but their sustained increase imposes a significant burden on the patient.…”