Gantner Marin L, Hazen Bethany C, Eury Elodie, Brown Erin L, Kralli Anastasia
Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037.
Endocrinology. 2016 Dec;157(12):4770-4781. doi: 10.1210/en.2016-1767. Epub 2016 Oct 20.
Brown adipose tissue (BAT) thermogenesis relies on a high abundance of mitochondria and the unique expression of the mitochondrial Uncoupling Protein 1 (UCP1), which uncouples substrate oxidation from ATP synthesis. Adrenergic stimulation of brown adipocytes activates UCP1-mediated thermogenesis; it also induces the expression of Ucp1 and other genes important for thermogenesis, thereby endowing adipocytes with higher oxidative and uncoupling capacities. Adipocyte mitochondrial biogenesis and oxidative capacity are controlled by multiple transcription factors, including the estrogen-related receptor (ERR)α. Whole-body ERRα knockout mice show decreased BAT mitochondrial content and oxidative function but normal induction of Ucp1 in response to cold. In addition to ERRα, brown adipocytes express ERRβ and ERRγ, 2 nuclear receptors that are highly similar to ERRα and whose function in adipocytes is largely unknown. To gain insights into the roles of all 3 ERRs, we assessed mitochondrial function and adrenergic responses in primary brown adipocytes lacking combinations of ERRs. We show that adipocytes lacking just ERRα, the most abundant ERR, show only mild mitochondrial defects. Adipocytes lacking ERRβ and ERRγ also show just mild defects. In contrast, adipocytes lacking all 3 ERRs have severe reductions in mitochondrial content and oxidative capacity. Moreover, adipocytes lacking all 3 ERRs have defects in the transcriptional and metabolic response to adrenergic stimulation, suggesting a wider role of ERRs in BAT function than previously appreciated. Our study shows that ERRs have a great capacity to compensate for each other in protecting mitochondrial function and the metabolic response to adrenergic signaling, processes vital to BAT function.
棕色脂肪组织（BAT）的产热依赖于大量的线粒体以及线粒体解偶联蛋白1（UCP1）的独特表达，UCP1可使底物氧化与ATP合成解偶联。对棕色脂肪细胞的肾上腺素能刺激可激活UCP1介导的产热；它还能诱导Ucp1以及其他对产热重要的基因的表达，从而赋予脂肪细胞更高的氧化和解偶联能力。脂肪细胞的线粒体生物合成和氧化能力受多种转录因子控制，包括雌激素相关受体（ERR）α。全身ERRα基因敲除小鼠的BAT线粒体含量和氧化功能降低，但对寒冷刺激时Ucp1的诱导正常。除了ERRα，棕色脂肪细胞还表达ERRβ和ERRγ，这两种核受体与ERRα高度相似，其在脂肪细胞中的功能 largely unknown。为了深入了解所有三种ERR的作用，我们评估了缺乏不同ERR组合的原代棕色脂肪细胞中的线粒体功能和肾上腺素能反应。我们发现，仅缺乏最丰富的ERRα的脂肪细胞仅表现出轻微的线粒体缺陷。缺乏ERRβ和ERRγ的脂肪细胞也仅表现出轻微缺陷。相比之下，缺乏所有三种ERR的脂肪细胞的线粒体含量和氧化能力严重降低。此外，缺乏所有三种ERR的脂肪细胞在对肾上腺素能刺激的转录和代谢反应方面存在缺陷，这表明ERR在BAT功能中的作用比以前认为的更广泛。我们的研究表明，ERR在保护线粒体功能和对肾上腺素能信号的代谢反应方面具有很大的相互补偿能力，而这些过程对BAT功能至关重要。 （注：“largely unknown”这里直接保留英文未翻译，因为可能是原文有误，正常应是“很大程度上未知”之类表述，按要求未添加说明直接翻译）
