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Cardiolipin Synthesis in Brown and Beige Fat Mitochondria Is Essential for Systemic Energy Homeostasis.
Cell Metabolism ( IF 27.7 ) Pub Date : 2018-Jul-03 , DOI: 10.1016/j.cmet.2018.05.003 Elahu G Sustarsic 1 , Tao Ma 1 , Matthew D Lynes 2 , Michael Larsen 3 , Iuliia Karavaeva 1 , Jesper F Havelund 4 , Carsten H Nielsen 5 , Mark P Jedrychowski 6 , Marta Moreno-Torres 4 , Morten Lundh 7 , Kaja Plucinska 7 , Naja Z Jespersen 8 , Trisha J Grevengoed 7 , Barbara Kramar 7 , Julia Peics 1 , Jakob B Hansen 1 , Farnaz Shamsi 2 , Isabel Forss 4 , Ditte Neess 4 , Susanne Keipert 9 , Jianing Wang 10 , Katharina Stohlmann 7 , Ivan Brandslund 11 , Cramer Christensen 12 , Marit E Jørgensen 13 , Allan Linneberg 14 , Oluf Pedersen 7 , Michael A Kiebish 15 , Klaus Qvortrup 3 , Xianlin Han 10 , Bente Klarlund Pedersen 16 , Martin Jastroch 9 , Susanne Mandrup 4 , Andreas Kjær 5 , Steven P Gygi 6 , Torben Hansen 7 , Matthew P Gillum 7 , Niels Grarup 7 , Brice Emanuelli 7 , Søren Nielsen 16 , Camilla Scheele 8 , Yu-Hua Tseng 2 , Nils J Færgeman 4 , Zachary Gerhart-Hines 1
Cell Metabolism ( IF 27.7 ) Pub Date : 2018-Jul-03 , DOI: 10.1016/j.cmet.2018.05.003 Elahu G Sustarsic 1 , Tao Ma 1 , Matthew D Lynes 2 , Michael Larsen 3 , Iuliia Karavaeva 1 , Jesper F Havelund 4 , Carsten H Nielsen 5 , Mark P Jedrychowski 6 , Marta Moreno-Torres 4 , Morten Lundh 7 , Kaja Plucinska 7 , Naja Z Jespersen 8 , Trisha J Grevengoed 7 , Barbara Kramar 7 , Julia Peics 1 , Jakob B Hansen 1 , Farnaz Shamsi 2 , Isabel Forss 4 , Ditte Neess 4 , Susanne Keipert 9 , Jianing Wang 10 , Katharina Stohlmann 7 , Ivan Brandslund 11 , Cramer Christensen 12 , Marit E Jørgensen 13 , Allan Linneberg 14 , Oluf Pedersen 7 , Michael A Kiebish 15 , Klaus Qvortrup 3 , Xianlin Han 10 , Bente Klarlund Pedersen 16 , Martin Jastroch 9 , Susanne Mandrup 4 , Andreas Kjær 5 , Steven P Gygi 6 , Torben Hansen 7 , Matthew P Gillum 7 , Niels Grarup 7 , Brice Emanuelli 7 , Søren Nielsen 16 , Camilla Scheele 8 , Yu-Hua Tseng 2 , Nils J Færgeman 4 , Zachary Gerhart-Hines 1
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Activation of energy expenditure in thermogenic fat is a promising strategy to improve metabolic health, yet the dynamic processes that evoke this response are poorly understood. Here we show that synthesis of the mitochondrial phospholipid cardiolipin is indispensable for stimulating and sustaining thermogenic fat function. Cardiolipin biosynthesis is robustly induced in brown and beige adipose upon cold exposure. Mimicking this response through overexpression of cardiolipin synthase (Crls1) enhances energy consumption in mouse and human adipocytes. Crls1 deficiency in thermogenic adipocytes diminishes inducible mitochondrial uncoupling and elicits a nuclear transcriptional response through endoplasmic reticulum stress-mediated retrograde communication. Cardiolipin depletion in brown and beige fat abolishes adipose thermogenesis and glucose uptake, which renders animals insulin resistant. We further identify a rare human CRLS1 variant associated with insulin resistance and show that adipose CRLS1 levels positively correlate with insulin sensitivity. Thus, adipose cardiolipin has a powerful impact on organismal energy homeostasis through thermogenic fat bioenergetics.
中文翻译：
棕色和米色脂肪线粒体中的心磷脂合成对于系统能量稳态至关重要。
激活产热脂肪中的能量消耗是改善代谢健康的一种有前途的策略，但引起这种反应的动态过程却知之甚少。在这里，我们表明线粒体磷脂心磷脂的合成对于刺激和维持产热脂肪功能是必不可少的。冷暴露后，棕色和米色脂肪中的心磷脂生物合成被强烈诱导。通过心磷脂合酶 (Crls1) 的过度表达来模仿这种反应，可以增强小鼠和人类脂肪细胞的能量消耗。产热脂肪细胞中的 Crls1 缺陷会减少可诱导的线粒体解偶联，并通过内质网应激介导的逆行通讯引发核转录反应。棕色和米色脂肪中的心磷脂消耗会消除脂肪生热作用和葡萄糖摄取，从而使动物产生胰岛素抵抗。我们进一步鉴定了一种与胰岛素抵抗相关的罕见人类 CRLS1 变异，并表明脂肪 CRLS1 水平与胰岛素敏感性呈正相关。因此，脂肪心磷脂通过生热脂肪生物能对有机体能量稳态具有强大的影响。
更新日期：2018-05-31
中文翻译：
棕色和米色脂肪线粒体中的心磷脂合成对于系统能量稳态至关重要。
激活产热脂肪中的能量消耗是改善代谢健康的一种有前途的策略，但引起这种反应的动态过程却知之甚少。在这里，我们表明线粒体磷脂心磷脂的合成对于刺激和维持产热脂肪功能是必不可少的。冷暴露后，棕色和米色脂肪中的心磷脂生物合成被强烈诱导。通过心磷脂合酶 (Crls1) 的过度表达来模仿这种反应，可以增强小鼠和人类脂肪细胞的能量消耗。产热脂肪细胞中的 Crls1 缺陷会减少可诱导的线粒体解偶联，并通过内质网应激介导的逆行通讯引发核转录反应。棕色和米色脂肪中的心磷脂消耗会消除脂肪生热作用和葡萄糖摄取，从而使动物产生胰岛素抵抗。我们进一步鉴定了一种与胰岛素抵抗相关的罕见人类 CRLS1 变异，并表明脂肪 CRLS1 水平与胰岛素敏感性呈正相关。因此，脂肪心磷脂通过生热脂肪生物能对有机体能量稳态具有强大的影响。
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