IL-6 Signal From the Bone Marrow is Required for the Browning of White Adipose Tissue Post Burn Injury

Abstract

The hypermetabolic stress response after burn contributes to multi-organ failure, sepsis, morbidity, and mortality. The cytokine interleukin 6 (IL-6) has been hypothesized to mediate not only white adipose tissue (WAT) browning in burns, but also other hypermetabolic conditions. In addition to its inflammatory effects, IL-6 also acts as a metabolic mediator that affects metabolic tissues. Therefore, we sought to uncover the origin of circulating IL-6 post burn injury that regulates WAT browning. WAT and sera samples were collected from both adult burn patients admitted to the Ross Tilley Burn Centre at Sunnybrook Hospital and mice subjected to a burn injury. Collected tissues were analyzed for browning markers and metabolic state via histology, gene expression, and resting energy expenditure. Increased WAT browning was observed in burn patients as well as mice subjected to burn injury. Circulating IL-6 levels were significantly elevated post burn injury in mice (<0.05) and in burn patients (<0.05), the latter of which was positively correlated with elevated REE. Genetic loss of whole body IL-6 in mice prevented burn-induced WAT browning. Transplanting IL-6 KO mice with bone marrow (BM) from wild type (WT) mice, recovered the browning phenotype in these mice, as evaluated by increased UCP-1 expression (<0.05). Conversely, transplanting irradiated WT mice with BM from IL-6 KO mice impaired burn induced browning with no significant expression of UCP-1. Together, our findings implicate BM derived IL-6 as the source controlling browning of WAT post burn injury. Thus, targeting IL-6 is a promising target for hypermetabolism in burns.

Energy metabolism in cachexia

“…In fact, hypermetabolism is commonly associated with inflammation in all forms of cachexia, be it cachexia associated with chronic kidney disease [135], AIDS [136], burn injury [137], rheumatism [138], or cancer [7,139].…”

Adipose tissue: between the extremes

“…Lipolysis and fatty acid release into the circulation have been shown to be elevated upon burn injury (Williams et al, 2009). Studies in mice have shown that IL-6 [which in case of burn injury is released from the bone marrow (Abdullahi et al, 2017)] has the potential to induce hypermetabolism, and IL-6 blockage can prevent adipose tissue defects in burn injury (Abdullahi et al, 2017). Similar to cachexia, burn injury often presents with elevated levels of inflammatory cytokines such as IL-6 (Abdullahi et al, 2017).…”

“…Interestingly, a recent study showed that adipose tissue loss due to septic burn injury could be traced back to a loss in AMPK-dependent inhibition of lipolysis in the adipose tissue (Diao et al, 2015). Interestingly, burn injury has recently been linked to increased adipose tissue browning Abdullahi et al, 2017), and multilocular, UCP1-positive adipocytes have been found in WAT from burn patients . Studies in mice have shown that IL-6 [which in case of burn injury is released from the bone marrow (Abdullahi et al, 2017)] has the potential to induce hypermetabolism, and IL-6 blockage can prevent adipose tissue defects in burn injury (Abdullahi et al, 2017).…”

“…Similar to cachexia, burn injury often presents with elevated levels of inflammatory cytokines such as IL-6 (Abdullahi et al, 2017). Studies in mice have shown that IL-6 [which in case of burn injury is released from the bone marrow (Abdullahi et al, 2017)] has the potential to induce hypermetabolism, and IL-6 blockage can prevent adipose tissue defects in burn injury (Abdullahi et al, 2017). Interestingly, burn injury has recently been linked to increased adipose tissue browning Abdullahi et al, 2017), and multilocular, UCP1-positive adipocytes have been found in WAT from burn patients .…”

The biochemical alterations underlying post-burn hypermetabolism

“…IL-6 has been reported to mediate the expression of IL-4R and augment the polarization of macrophages, suggesting that the aforementioned reduction in browning caused by clodronate may in fact have been a result of reduced IL-6 signalling [124]. Indeed, IL-6 levels are significantly elevated in burn patients and gene knock-outs of this cytokine prevent WAT browning, a phenomenon rescued with WT administration of IL-6 [32], [118] and [125]. Other molecular modulators of browning such as peroxisome proliferator-activated receptors (PPAR-y) have also been proposed; expression of BAT markers such as increased UCP-1 production have been reported with ginsenoside Rb1, lactate, thymol and erythropoietin activity [126], [127], [128] and [129].…”