Mitochondrial regulation of energy efficiency

描述（由申请人提供）：棕色脂肪组织（BAT）具有独特的开启解偶联，导致营养消耗和产热的能力。因此，扩大BAT被认为是减少人类肥胖的潜在策略。已经开发了增加BAT质量的新方法，但是完全分化的BAT通过生热耗散能量的能力仍然依赖于肾上腺素能刺激。因此，为了获得治疗效果，BAT的扩大必须辅之以激活BAT解耦和能量耗散的新途径。我们的研究表明，除了脂肪分解外，肾上腺素能刺激还会引起线粒体网络结构的急性和强烈变化。线粒体的这些变化增加了游离脂肪酸（FFA）诱导解偶联和能量耗散的能力。我们假设线粒体动力学的变化通过增强FFA激活UCP1的能力和招募PTP作为次要的解偶联机制，作为去甲肾上腺素诱导解偶联的放大途径。为了解决这一假设，我们将(i)研究小鼠棕色脂肪细胞（BA）和人类白脂肪细胞（白色中的棕色）线粒体动力学的NE-unique变化，并确定这些影响的分子介质，（ii）量化线粒体动力学在体外和体内作为人类白脂肪细胞和小鼠BA能量耗散的扩增和增敏途径的程度。（iii）确定线粒体动力学变化放大能量消耗和增加BAT对FFA敏感性的机制。这项研究将证明，线粒体动力学是一个潜在的治疗干预点，通过它可以在没有肾上腺素能刺激的情况下，在血浆脂肪酸水平上激活BA解偶联。两种靶向线粒体动力学的药理学方法也将被测试，作为该方法的概念证明，验证线粒体动力学变化对BA解耦和能量耗散的影响。

DESCRIPTION (provided by applicant): Brown adipose tissue (BAT) is unique in its ability to acutely turn on uncoupling, leading to nutrient consumption and thermogenesis. As such, expansion of BAT is considered a potential strategy to reduce obesity in humans. New approaches to increase BAT mass have been developed, however the ability of fully differentiated BAT to dissipate energy by thermogenesis still remains dependent on adrenergic stimulation. Therefore, to obtain therapeutic benefit, expansion of BAT must be complemented by new approaches to activate BAT uncoupling and energy dissipation. Our studies indicate that in addition to lipolysis, adrenergic stimulation induces acute and robust changes to mitochondrial network architecture. These changes to mitochondria increase the ability of free fatty acids (FFA) to induce uncoupling and energy dissipation. We hypothesize that changes to mitochondrial dynamics serve as an amplification pathway for norepinephrine-induced uncoupling by enhancing the ability of FFA to activate UCP1 and by recruiting PTP as a secondary uncoupling mechanism. To address this hypothesis we will (i) study NE-unique changes to mitochondrial dynamics in the mouse brown adipocytes (BA) and human brite (brown in white) adipocytes, and determine the molecular mediators of these effects, (ii) quantify the extent to which mitochondrial dynamics acts as an amplification and sensitization pathway for energy dissipation in human brite and mouse BA in vitro and in vivo, and (iii) determine the mechanism by which changes to mitochondrial dynamics amplifies energy expenditure and increases sensitivity of BAT to FFA. This study will demonstrate that mitochondrial dynamics is a potential therapeutic point of intervention through which activation of BA uncoupling can be achieved at plasma levels of fatty acids, in the absence of adrenergic stimulation. Two pharmacological approaches to target mitochondrial dynamics will also be tested as a proof of concept for this approach, verifying the impact of changes to mitochondrial dynamics on BA uncoupling and energy dissipation.