Helmholtz Institute for Metabolic, Obesity and Vascular Research (HI-MAG) of the Helmholtz Zentrum München at the University of Leipzig and University Hospital Leipzig, Leipzig, Germany.
Medical Department III - Endocrinology, Nephrology, Rheumatology, University of Leipzig Medical Center, Leipzig, Germany.
Clin Transl Med. 2022 Dec;12(12):e1108. doi: 10.1002/ctm2.1108.
Recruitment and activation of brown adipose tissue (BAT) results in increased energy expenditure (EE) via thermogenesis and represents an intriguing therapeutic approach to combat obesity and treat associated diseases. Thermogenesis requires an increased and efficient supply of energy substrates and oxygen to the BAT. The hemoprotein myoglobin (MB) is primarily expressed in heart and skeletal muscle fibres, where it facilitates oxygen storage and flux to the mitochondria during exercise. In the last years, further contributions of MB have been assigned to the scavenging of reactive oxygen species (ROS), the regulation of cellular nitric oxide (NO) levels and also lipid binding. There is a substantial expression of MB in BAT, which is induced during brown adipocyte differentiation and BAT activation. This suggests MB as a previously unrecognized player in BAT contributing to thermogenesis.
This study analyzed the consequences of MB expression in BAT on mitochondrial function and thermogenesis in vitro and in vivo. Using MB overexpressing, knockdown or knockout adipocytes, we show that expression levels of MB control brown adipocyte mitochondrial respiratory capacity and acute response to adrenergic stimulation, signalling and lipolysis. Overexpression in white adipocytes also increases their metabolic activity. Mutation of lipid interacting residues in MB abolished these beneficial effects of MB. In vivo, whole-body MB knockout resulted in impaired thermoregulation and cold- as well as drug-induced BAT activation in mice. In humans, MB is differentially expressed in subcutaneous (SC) and visceral (VIS) adipose tissue (AT) depots, differentially regulated by the state of obesity and higher expressed in AT samples that exhibit higher thermogenic potential.
These data demonstrate for the first time a functional relevance of MBs lipid binding properties and establish MB as an important regulatory element of thermogenic capacity in brown and likely beige adipocytes.
棕色脂肪组织（BAT）的募集和激活通过产热导致能量消耗增加，这代表了一种有吸引力的治疗肥胖症和治疗相关疾病的方法。产热需要增加和有效地向 BAT 供应能量底物和氧气。血红素蛋白肌红蛋白（MB）主要在心脏和骨骼肌纤维中表达，在运动过程中，它促进氧气储存和向线粒体的流动。在过去的几年中，MB 的进一步作用被分配到清除活性氧（ROS）、调节细胞中一氧化氮（NO）水平以及脂质结合。BAT 中有大量的 MB 表达，在棕色脂肪细胞分化和 BAT 激活过程中被诱导。这表明 MB 是 BAT 中以前未被识别的产热调节剂。
本研究分析了 BAT 中 MB 表达对线粒体功能和产热的体外和体内影响。使用 MB 过表达、敲低或敲除脂肪细胞，我们表明 MB 的表达水平控制棕色脂肪细胞线粒体呼吸能力和对肾上腺素刺激、信号转导和脂肪分解的急性反应。在白色脂肪细胞中的过表达也增加了它们的代谢活性。MB 中与脂质相互作用的残基发生突变会消除 MB 的这些有益作用。在体内，全身 MB 敲除导致小鼠的体温调节受损，以及冷诱导和药物诱导的 BAT 激活受损。在人类中，MB 在皮下（SC）和内脏（VIS）脂肪组织（AT）中差异表达，其状态受肥胖调节，在表现出更高产热潜力的 AT 样本中表达更高。
这些数据首次证明了 MB 的脂质结合特性的功能相关性，并确立了 MB 作为棕色和可能米色脂肪细胞产热能力的重要调节元件。
