Department of Animal Sciences, Purdue University, West Lafayette, Indiana, USA.
Department of Biological Sciences, Purdue University, West Lafayette, Indiana, USA.
FASEB J. 2021 Nov;35(11):e21965. doi: 10.1096/fj.202100597R.
Obesity and metabolic disorders caused by energy surplus pose an increasing concern within the global population. Brown adipose tissue (BAT) dissipates energy through mitochondrial non-shivering thermogenesis, thus representing a powerful agent against obesity. Here we explore the novel role of a mitochondrial outer membrane protein, LETM1-domain containing 1 (LETMD1), in BAT. We generated a knockout (Letmd1 ) mouse model and analyzed BAT morphology, function and gene expression under various physiological conditions. While the Letmd1 mice are born normally and have normal morphology and body weight, they lose multilocular brown adipocytes completely and have diminished mitochondrial abundance, DNA copy number, cristae structure, and thermogenic gene expression in the intrascapular BAT, associated with elevated reactive oxidative stress. In consequence, the Letmd1 mice fail to maintain body temperature in response to acute cold exposure without food and become hypothermic within 4 h. Although the cold-exposed Letmd1 mice can maintain body temperature in the presence of food, they cannot upregulate expression of uncoupling protein 1 (UCP1) and convert white to beige adipocytes, nor can they respond to adrenergic stimulation. These results demonstrate that LETMD1 is essential for mitochondrial structure and function, and thermogenesis of brown adipocytes.
能量过剩导致的肥胖和代谢紊乱在全球人群中日益受到关注。棕色脂肪组织（BAT）通过线粒体非颤抖性产热来消耗能量，因此是对抗肥胖的有力手段。在这里，我们探索了一种线粒体外膜蛋白 LETM1 结构域包含蛋白 1（LETMD1）在 BAT 中的新作用。我们生成了 Letmd1 敲除（Letmd1 ）小鼠模型，并在各种生理条件下分析了 BAT 的形态、功能和基因表达。虽然 Letmd1 小鼠正常出生，形态和体重正常，但它们完全失去多房性棕色脂肪细胞，线粒体丰度、DNA 拷贝数、嵴结构和肩胛间 BAT 的产热基因表达减少，伴随着氧化应激反应升高。结果，Letmd1 小鼠在没有食物的急性冷暴露下无法维持体温，在 4 小时内体温过低。尽管寒冷暴露的 Letmd1 小鼠在有食物的情况下可以维持体温，但它们不能上调解偶联蛋白 1（UCP1）的表达并将白色脂肪转化为米色脂肪细胞，也不能对肾上腺素刺激做出反应。这些结果表明 LETMD1 对于棕色脂肪细胞的线粒体结构和功能以及产热是必不可少的。
