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。BernerdinaliSeip先天性脂肪营养不良(BSCL)2型(BSCL2,又名SEIPIN),脂肪代谢障碍相关蛋白,已经证明棕色脂肪生成不需要,但它已被证明是必不可少的围产期BAT的发展。然而,它在成熟的BAT维护和产热编程中的作用仍然知之甚少。
我们使Bscl2f/f和Bscl2UCP1-BKO(BKO)小鼠通过UCP1启动子驱动的Cre,药理学和饮食干预,以挑战BAT功能和重新编程。我们进行了生理,BAT的分子和转录组学分析。
成熟棕色脂肪细胞中BSCL2的缺失增加了BAT中不依赖交感神经系统的cAMP/蛋白激酶A(PKA)信号。这种活化降低了BAT甘油三酯的含量和质量,并且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引起的肥胖。令人惊讶的是,尽管cAMP/PKA激活,但BKO小鼠对急性和慢性感冒挑战的反应受损。当遭受慢性寒冷暴露或施用β3-肾上腺素能激动剂时,CL316,243,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。转录组学分析显示病理性BAT重塑伴有炎症和纤维化,BKO小鼠的慢性热激发进一步加剧了这种情况。机械上,我们在21°C的BKO小鼠的BAT中发现了异常的线粒体形状和功能;以及慢性热损伤后线粒体DNA耗竭和坏死介导的棕色脂肪细胞死亡。
BSCL2介导的BAT内的脂质分解代谢对于激活和静止期间的成熟棕色脂肪细胞功能和存活都是至关重要的。BSCL2是成熟棕色脂肪细胞线粒体代谢的重要调节因子,坏死和适应性产热。
Understanding 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.
We subjected Bscl2f/f and Bscl2UCP1-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.
The 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.
BSCL2-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.