Berardinelli-Seip congenital lipodystrophy 2/SEIPIN determines brown adipose tissue maintenance and thermogenic programing.
Berardinelli-Seip congenital lipodystrophy 2/SEIPIN determines brown adipose tissue maintenance and thermogenic programing.
复制标题
Berardinelli-Seip 先天性脂肪营养不良 2/SEIPIN 决定棕色脂肪组织的维持和产热程序。
DOI：
10.1016/j.molmet.2020.02.014
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发表时间：
2020
影响因子：
8.1
通讯作者：
Chen,Weiqin
中科院分区：
文献类型：
--
作者：
Zhou,Hongyi;Xu,Cheng;Lee,Hakjoo;Yoon,Yisang;Chen,Weiqin
了解控制棕色脂肪组织（BAT）质量和功能的机制对于我们理解能量稳态的破坏如何导致肥胖至关重要。Bernerdinali Seip先天性脂肪营养不良（BSCL）2型（BSCL 2，a.k.a. SEIPIN），一种脂肪营养不良相关蛋白，已被证明不是棕色脂肪生成所必需的，但已被证明是围产期BAT发育所必需的。然而，它在成熟的BAT维护和产热programming的作用仍然知之甚少。MethodsWe subjectedBscl 2f/fandBscl 2UCP 1-BKO（BKO）小鼠与棕色脂肪特定的损失BSCL 2通过UCP 1启动子驱动的Cre环境，药理学和饮食干预挑战BAT的功能和重编程。我们进行了生理，分子和转录组分析BAT。结果BSCL 2在成熟的棕色脂肪细胞中的缺失增加了交感神经系统独立的cAMP/蛋白激酶A（PKA）信号在BAT。这种激活降低BAT甘油三酯含量和质量，并足以降低血浆甘油三酯，但不足以对抗热中性和高脂肪饮食诱导的肥胖。令人惊讶的是，尽管cAMP/PKA激活，BKO小鼠对急性和慢性寒冷挑战的反应受损。当经历慢性冷暴露或给予β3-肾上腺素能激动剂CL 316，243时，BKO小鼠未能诱导BAT募集，并且经历了显著的棕色脂肪细胞损失。转录组学分析揭示了具有炎症和纤维化的病理性BAT重塑，其在BKO小鼠中通过慢性产热激发进一步加剧。结论BSCL 2介导的脂代谢紊乱对成熟棕色脂肪细胞的功能和存活起重要作用。BSCL 2是成熟棕色脂肪细胞线粒体代谢、坏死性凋亡和适应性产热的重要调节因子。
ObjectiveUnderstanding the mechanisms that control brown adipose tissue (BAT) mass and functionality is crucial for our understanding of how the disruption of energy homeostasis leads to obesity. Bernerdinali Seip Congenital Lipodystrophy (BSCL) type 2 (BSCL2, a.k.a. SEIPIN), a lipodystrophy-associated protein, has been shown to not be required for brown adipogenesis, but it has been shown to be essential for perinatal BAT development. However, its role in mature BAT maintenance and thermogenic programing remains poorly understood.MethodsWe subjectedBscl2f/fandBscl2UCP1-BKO(BKO) mice with a brown adipose-specific loss of BSCL2 through UCP1 promoter-driven Cre to environmental, pharmacological and diet interventions to challenge BAT functionality and reprogramming. We carried out physiological, molecular and transcriptomic analyses of BAT.ResultsThe deletion of BSCL2 in mature brown adipocytes increased sympathetic nervous system-independent cAMP/protein kinase A (PKA) signaling in BAT. Such activation reduced BAT triglyceride content and mass and was sufficient to reduce plasma triglyceride, but not enough to combat thermoneutral and high fat diet-induced obesity. Surprisingly, BKO mice displayed an impaired response to acute and chronic cold challenges despite cAMP/PKA activation. When subjected to chronic cold exposure or the administration of a β3-adrenergic agonist, CL 316,243, BKO mice failed to induce BAT recruitment and underwent dramatic brown adipocyte loss. Transcriptomic analysis revealed pathological BAT remodeling with inflammation and fibrosis, which was further exacerbated by a chronic thermogenic challenge in BKO mice. Mechanistically, we found abnormal mitochondrial shapes and function in BAT of BKO mice housed at 21 °C; as well as mitochondrial DNA depletion and necroptotic-mediated brown adipocyte death after chronic thermogenic insult.ConclusionBSCL2-mediated lipid catabolism within BAT is crucial for mature brown adipocyte function and survival both during times of activation and quiescence. BSCL2 is an important regulator of mature brown adipocyte mitochondrial metabolism, necroptosis and thus adaptive thermogenesis.