Department of Nutrition and Health Sciences, University of Nebraska-Lincoln, Lincoln, NE, USA.
Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, 183T11, P.O. Box 22452, Riyadh, 11495, Saudi Arabia.
Inflammation. 2018 Mar;41(2):626-642. doi: 10.1007/s10753-017-0718-y.
Adipose tissue expansion is accompanied by infiltration and accumulation of pro-inflammatory macrophages, which links obesity to pathologic conditions such as type 2 diabetes. However, little is known regarding the role of pro-inflammatory adipose tissue remodeling in the thermogenic activation of brown/beige fat. Here, we investigated the effect of pattern recognition receptors (PRR) activation in macrophages, especially the toll-like receptor 4 (TLR4) and Nod-like receptor 3 (NLRP3), on white adipocyte browning. We report that TLR4 activation by lipopolysaccharide repressed white adipocyte browning in response to β3-adrenergic receptor activation and caused ROS production and mitochondrial dysfunction, while genetic deletion of TLR4 protected mitochondrial function and thermogenesis. In addition, activation of NLRP3 inflammasome in macrophages attenuated UCP1 induction and mitochondrial respiration in cultures of primary adipocytes, while the absence of NLRP3 protected UCP1 in adipocytes. The effect of NLRP3 inflammasome activation on browning was mediated by IL-1β signaling, as blocking IL-1 receptor in adipocytes protected thermogenesis. We also report that IL-1β interferes with thermogenesis via oxidative stress stimulation and mitochondrial dysfunction as we observed a statistically significant increase in ROS production, decrease in SOD enzyme activity, and increase in mitochondrial depolarization in adipocytes treated with IL-1β. Collectively, we demonstrated that inflammatory response to obesity, such as TLR4 and NLRP3 inflammasome activation as well as IL-1β secretion, attenuates β3-adrenoreceptor-induced beige adipocyte formation via oxidative stress and mitochondrial dysfunction. Our findings provide insights into targeting innate inflammatory system for enhancement of the adaptive thermogenesis against obesity.
脂肪组织扩张伴随着促炎巨噬细胞的浸润和积累，这将肥胖与 2 型糖尿病等病理状况联系起来。然而，关于促炎脂肪组织重塑在棕色/米色脂肪的产热激活中的作用知之甚少。在这里，我们研究了模式识别受体（PRR）在巨噬细胞中的激活作用，特别是 Toll 样受体 4（TLR4）和 Nod 样受体 3（NLRP3），对白色脂肪细胞棕色化的影响。我们报告称，脂多糖（LPS）激活 TLR4 抑制了β3-肾上腺素能受体激活后白色脂肪细胞的棕色化，并导致 ROS 产生和线粒体功能障碍，而 TLR4 的基因缺失则保护了线粒体功能和产热。此外，巨噬细胞中 NLRP3 炎性小体的激活减弱了原代脂肪细胞培养物中 UCP1 的诱导和线粒体呼吸作用，而 NLRP3 的缺失则保护了脂肪细胞中的 UCP1。NLRP3 炎性小体激活对棕色化的影响是通过 IL-1β 信号转导介导的，因为阻断脂肪细胞中的 IL-1 受体可保护产热。我们还报告称，IL-1β 通过氧化应激刺激和线粒体功能障碍干扰产热，因为我们观察到用 IL-1β 处理的脂肪细胞中 ROS 产生、SOD 酶活性降低和线粒体去极化增加均具有统计学意义。总之，我们证明了肥胖引起的炎症反应，如 TLR4 和 NLRP3 炎性小体的激活以及 IL-1β 的分泌，通过氧化应激和线粒体功能障碍减弱了β3-肾上腺素能受体诱导的米色脂肪形成。我们的研究结果为针对先天炎症系统以增强针对肥胖的适应性产热提供了新的见解。
