Objective

Beclin1 is a core molecule of the macroautophagy machinery. Although dysregulation of macroautophagy is known to be involved in metabolic disorders, the function of Beclin1 in adipocyte metabolism has not been investigated. In the present study, we aimed to study the role of Beclin1 in lipolysis and mitochondrial homeostasis of adipocytes.

Methods

Autophagic flux during lipolysis was examined in adipocytes cultured in vitro and in the adipose tissue of mice. Adipocyte-specific Beclin1 knockout (KO) mice were used to investigate the activities of Beclin1 in adipose tissues.

Results

cAMP/PKA signaling increased the autophagic flux in adipocytes differentiated from C3H10T1/2 cells. In vivo autophagic flux was higher in the brown adipose tissue (BAT) than that in the white adipose tissue and was further increased by the β3 adrenergic receptor agonist CL316243. In addition, surgical denervation of BAT greatly reduced autophagic flux, indicating that sympathetic nerve activity is a major regulator of tissue autophagy. Adipocyte-specific KO of Beclin1 led to a hypertrophic enlargement of lipid droplets in BAT and impaired CL316243-induced lipolysis/lipid mobilization and energy expenditure. While short-term effects of Beclin1 deletion were characterized by an increase in mitochondrial proteins, long-term Beclin1 deletion led to severe disruption of autophagy, resulting in mitochondrial loss, and dramatically reduced the expression of genes involved in lipid metabolism. Consequently, adipose tissue underwent increased activation of cell death signaling pathways, macrophage recruitment, and inflammation, particularly in BAT.

Conclusions

The present study demonstrates the critical roles of Beclin1 in the maintenance of lipid metabolism and mitochondrial homeostasis in adipose tissues.

中文翻译：

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特定于脂肪细胞的Beclin1缺失会损害脂肪组织中的脂解作用和线粒体完整性。

目的

Beclin1是宏观自噬机制的核心分子。尽管已知巨噬细胞吞噬失调与代谢紊乱有关，但尚未研究Beclin1在脂肪细胞代谢中的功能。在本研究中，我们旨在研究Beclin1在脂肪细胞的脂解和线粒体稳态中的作用。

方法

在体外培养的脂肪细胞和小鼠脂肪组织中检查了脂解过程中的自噬通量。脂肪细胞特异性Beclin1基因敲除（KO）小鼠用于研究Beclin1在脂肪组织中的活性。

结果

cAMP / PKA信号增加了从C3H10T1 / 2细胞分化出的脂肪细胞中的自噬通量。体内的自噬通量在棕色脂肪组织（BAT）中高于在白色脂肪组织中，并且被β3肾上腺素能受体激动剂CL316243进一步提高。另外，BAT的手术去神经支配大大减少了自噬通量，表明交感神经活动是组织自噬的主要调节剂。Beclin1的脂肪细胞特异性KO导致BAT中脂质滴的肥大性增大，并损害CL316243诱导的脂解/脂质动员和能量消耗。虽然Beclin1缺失的短期效应以线粒体蛋白的增加为特征，但长期Beclin1缺失会导致自噬的严重破坏，从而导致线粒体丢失，并大大减少了参与脂质代谢的基因的表达。因此，脂肪组织的细胞死亡信号通路，巨噬细胞募集和炎症的激活增加，尤其是在BAT中。

结论

本研究证明了Beclin1在维持脂肪组织中脂质代谢和线粒体稳态方面的关键作用。