Objective

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.

Methods

We subjected Bscl2^f/f and Bscl2^UCP1-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.

Results

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.

Conclusion

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.

中文翻译：

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Berardinelli-Seip 先天性脂肪代谢障碍 2/SEIPIN 决定了棕色脂肪组织的维持和产热编程。

客观的

了解控制棕色脂肪组织 (BAT) 质量和功能的机制对于我们了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（BSCL2，又名 SEIPIN）是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，但已被证明对围产期 BAT 发育至关重要。然而，它在成熟 BAT 维护和产热编程中的作用仍然知之甚少。

方法

我们通过 UCP1 启动子驱动的 Cre 对 Bscl2 f/f和^Bscl2 UCP1 - ^{BKO (BKO) 小鼠进行环境、药理学和饮食干预，以挑战 BAT 功能和重编程，使棕色脂肪特异性 BSCL2 缺失。}我们对 BAT 进行了生理、分子和转录组学分析。

结果

成熟棕色脂肪细胞中 BSCL2 的缺失增加了 BAT 中交感神经系统非依赖性 cAMP/蛋白激酶 A (PKA) 信号传导。这种激活降低了 BAT 甘油三酯含量和质量，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 小鼠对急性和慢性寒冷挑战的反应受损。当长期暴露于寒冷或给予 β3-肾上腺素能激动剂 CL 316,243 时，BKO 小鼠未能诱导 BAT 募集并经历了显着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，BKO 小鼠的慢性产热挑战进一步加剧了这种重塑。从机械上讲，我们在 21 °C 饲养的 BKO 小鼠的 BAT 中发现了异常的线粒体形状和功能；以及慢性产热损伤后线粒体 DNA 耗竭和坏死介导的棕色脂肪细胞死亡。

结论

BAT 中 BSCL2 介导的脂质分解代谢对于成熟棕色脂肪细胞的功能以及在激活和静止期间的存活至关重要。BSCL2 是成熟棕色脂肪细胞线粒体代谢、坏死性凋亡以及适应性产热的重要调节因子。