背景:棕色脂肪组织(BAT)的募集和激活导致通过产热增加的能量消耗(EE),并代表了一种有趣的治疗方法来对抗肥胖和治疗相关疾病。产热需要向BAT提供增加且有效的能量底物和氧气。血红蛋白肌红蛋白(MB)主要在心脏和骨骼肌纤维中表达,在运动过程中,它有助于氧气储存和流向线粒体。在过去的几年里,MB的进一步贡献已被指定为清除活性氧(ROS),细胞一氧化氮(NO)水平的调节以及脂质结合。MB在BAT中大量表达,在棕色脂肪细胞分化和BAT激活过程中诱导。这表明MB是BAT中以前未被认可的参与者,有助于产热。
结果:这项研究分析了BAT中MB表达对线粒体功能和体外和体内产热的影响。使用MB过度表达,敲除或敲除脂肪细胞,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能刺激的急性反应,信号和脂肪分解。白色脂肪细胞中的过表达也增加了它们的代谢活性。MB中脂质相互作用残基的突变消除了MB的这些有益作用。在体内,全身MB敲除导致小鼠体温调节受损和寒冷以及药物诱导的BAT激活。在人类中,MB在皮下(SC)和内脏(VIS)脂肪组织(AT)仓库中差异表达,受肥胖状态的差异调节,在表现出较高产热潜力的AT样品中表达较高。
结论:这些数据首次证明了MBs脂质结合特性的功能相关性,并确立了MB作为棕色和可能的米色脂肪细胞产热能力的重要调节元件。
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.