The role of phosphatidylserine-decarboxylase for brown adipose tissue formation and function

哺乳动物脂肪组织可分为白色和棕色脂肪组织(BAT)。棕色脂肪细胞含有几个小的脂滴，可以通过非颤抖产热产生热量来维持稳定的体温，这是由位于线粒体膜内的解偶联蛋白1(UCP1)介导的。因为BAT产热的底物是葡萄糖和游离脂肪酸，所以BAT参与了全身葡萄糖和脂肪的动态平衡。事实上，人类蝙蝠的存在和活动与更高的能量消耗、更低的肥胖率和更低的胰岛素抵抗风险相关。因此，激活棕色脂肪细胞产热被认为是一种有前途的增加能量消耗的策略。此外，识别调控棕色脂肪细胞发育和产热的机制可能有助于对抗代谢病理和疾病。我们和其他人之前已经证明，膜脂成分在细胞和亚细胞水平上被精确控制，细胞类型特定，并适应细胞功能。膜脂组成对膜的物理性质有重要影响，包括膜脂的堆积密度和流动性。内质网(ER)是参与磷脂合成的主要细胞器，其次是高尔基体和线粒体。细胞内的磷脂酰乙醇胺(PE)是一种主要的细胞膜脂质，由线粒体中的磷脂酰丝氨酸脱羧酶(PISD)产生。由于PISD的活性与小鼠脂肪组织褐变和UCP1介导的棕色脂肪细胞呼吸有关，我们认为PlSD是蝙蝠线粒体生物能量学的关键调节因子。因此，该研究计划的主要目的是研究PISD与体内非颤抖产热的生理学和病理生理学的相关性，以及确定PISD介导的线粒体生物能量学调节的机制。

Mammalian adipose tissue can be categorized in white and brown adipose tissue (BAT). Brown adipocytes contain several small lipid droplets and can generate heat to maintain a stable body temperature by non-shivering thermogenesis, which is mediated by uncoupling protein 1 (UCP1) located in the inner mitochondrial membrane. Because substrates for BAT thermogenesis are glucose and free fatty acids, BAT is involved in systemic glucose and lipid homeostasis. Indeed, the presence and activity of human BAT correlates with higher energy expenditure, lower adiposity, and reduced risk of insulin resistance. Therefore, activation of brown adipocyte thermogenesis is considered a promising strategy to increase energy expenditure. Further, the identification of mechanisms regulating brown adipocyte development and thermogenesis might be useful to combat metabolic pathologies and diseases.We and others have previously shown that the membrane lipid composition is precisely controlled on the cellular and subcellular level, cell type-specific and adapted to cellular functions. The lipid composition of membranes significantly influences physical membrane properties including lipid packing density and fluidity. The endoplasmic reticulum (ER) is the prime organelle involved in phospholipid synthesis, followed by the Golgi apparatus and mitochondria. A significant fraction of cellular phosphatidylethanolamine (PE), a major cell membrane lipid, is generated from phosphatidylserine (PS) by phosphatidylserine-decarboxylase (PISD) in mitochondria.Because in our preliminary data PISD activity correlates with murine adipose tissue browning and UCP1-mediated respiration in brown adipocytes, we propose that PlSD is a key regulator of mitochondrial bioenergetics in BAT. Therefore, the main objectives of the proposed research program are to investigate the physiological and pathophysiological relevance of PISD for non-shivering thermogenesis in vivo as well as to identify the mechanism underlying PISD-mediated regulation of mitochondrial bioenergetics.