University of Toronto, Toronto, ON, Canada.
Biological Sciences, Sunnybrook Research Institute, Toronto, ON, Canada.
Ann Surg. 2019 Mar;269(3):554-563. doi: 10.1097/SLA.0000000000002465.
The aim of this study was to uncover the mediators and mechanistic events that facilitate the browning of white adipose tissue (WAT) in response to burns.
In hypermetabolic patients (eg, burns, cancer), the browning of WAT has presented substantial clinical challenges related to cachexia, atherosclerosis, and poor clinical outcomes. Browning of the adipose tissue has recently been found to induce and sustain hypermetabolism. Although browning appears central in trauma-, burn-, or cancer-induced hypermetabolic catabolism, the mediators are essentially unknown.
WAT and blood samples were collected from patients admitted to the Ross Tilley Burn Centre at Sunnybrook Hospital. Wild type, CCR2 KO, and interleukin (IL)-6 KO male mice were purchased from Jax laboratories and subjected to a 30% total body surface area burn injury. WAT and serum collected were analyzed for browning markers, macrophages, and metabolic state via histology, gene expression, and mitochondrial respiration.
In the present study, we show that burn-induced browning is associated with an increased macrophage infiltration, with a greater type 2 macrophage profile in the fat of burn patients. Similar to our clinical findings in burn patients, both an increase in macrophage recruitment and a type 2 macrophage profile were also observed in post burn mice. Genetic loss of the chemokine CCR2 responsible for macrophage migration to the adipose impairs burn-induced browning. Mechanistically, we show that macrophages recruited to burn-stressed subcutaneous WAT (sWAT) undergo alternative activation to induce tyrosine hydroxylase expression and catecholamine production mediated by IL-6, factors required for browning of sWAT.
Together, our findings uncover macrophages as the key instigators and missing link in trauma-induced browning.
本研究旨在揭示促进白色脂肪组织（WAT）褐变以应对烧伤的介导因子和机制事件。
在高代谢患者（例如烧伤、癌症）中，WAT 的褐变与恶病质、动脉粥样硬化和不良临床结局相关，这提出了重大的临床挑战。最近发现脂肪组织的褐变可诱导和维持高代谢。尽管在创伤、烧伤或癌症引起的高代谢分解代谢中，褐变似乎处于中心地位，但介导因子基本上是未知的。
从入住 Sunnybrook 医院 Ross Tilley 烧伤中心的患者中采集 WAT 和血液样本。从 Jackson 实验室购买野生型、CCR2 KO 和白细胞介素（IL）-6 KO 雄性小鼠，并对其进行 30%全身体表面积烧伤损伤。通过组织学、基因表达和线粒体呼吸分析 WAT 和血清中的褐变标志物、巨噬细胞和代谢状态。
在本研究中，我们表明，烧伤诱导的褐变与巨噬细胞浸润增加相关，烧伤患者脂肪中的巨噬细胞呈 2 型特征更为明显。与我们在烧伤患者中的临床发现类似，在烧伤后小鼠中也观察到巨噬细胞募集增加和 2 型巨噬细胞表型。负责巨噬细胞迁移到脂肪的趋化因子 CCR2 的遗传缺失会损害烧伤诱导的褐变。从机制上讲，我们表明募集到烧伤应激下的皮下 WAT（sWAT）的巨噬细胞发生了替代激活，以诱导酪氨酸羟化酶表达和儿茶酚胺产生，这是 sWAT 褐变所必需的因子。
总之，我们的研究结果揭示了巨噬细胞是创伤诱导褐变的关键启动子和缺失环节。
