Complementary Roles of Estrogen-Related Receptors in Brown Adipocyte Thermogenic Function
Complementary Roles of Estrogen-Related Receptors in Brown Adipocyte Thermogenic Function
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雌激素相关受体在棕色脂肪细胞产热功能中的互补作用
DOI：
10.1210/en.2016-1767
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发表时间：
2016-12-01
期刊：
影响因子：
4.8
通讯作者：
Kralli, Anastasia
中科院分区：
文献类型：
--
作者：
Gantner, Marin L.;Hazen, Bethany C.;Kralli, Anastasia
棕色脂肪组织 (BAT) 产热依赖于高丰度的线粒体和线粒体解偶联蛋白 1 (UCP1) 的独特表达，该蛋白将底物氧化与 ATP 合成解偶联。棕色脂肪细胞的肾上腺素刺激激活 UCP1 介导的生热作用；它还诱导 Ucp1 和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。脂肪细胞线粒体生物合成和氧化能力由多种转录因子控制，包括雌激素相关受体 (ERR)α。全身 ERR α 基因敲除小鼠表现出 BAT 线粒体含量和氧化功能下降，但对寒冷反应的 Ucp1 诱导正常。除了 ERR α 之外，棕色脂肪细胞还表达 ERR β 和 ERR γ，这两种核受体与 ERR α 高度相似，并且其在脂肪细胞中的功能很大程度上未知。为了深入了解所有 3 个 ERR 的作用，我们评估了缺乏 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 ERR α（最丰富的 ERR）的脂肪细胞仅表现出轻微的线粒体缺陷。缺乏 ERR beta 和 ERR gamma 的脂肪细胞也仅表现出轻微的缺陷。相反，缺乏全部 3 个 ERR 的脂肪细胞线粒体含量和氧化能力严重降低。此外，缺乏全部 3 个 ERR 的脂肪细胞在对肾上腺素能刺激的转录和代谢反应中存在缺陷，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信号传导的代谢反应（对 BAT 功能至关重要的过程）方面具有强大的相互补偿能力。
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)alpha. Whole-body ERR alpha knockout mice show decreased BAT mitochondrial content and oxidative function but normal induction of Ucp1 in response to cold. In addition to ERR alpha, brown adipocytes express ERR beta and ERR gamma, 2 nuclear receptors that are highly similar to ERR alpha 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 ERR alpha, the most abundant ERR, show only mild mitochondrial defects. Adipocytes lacking ERR beta and ERR gamma 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 transcriptionalandmetabolic 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.