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首页> 美国卫生研究院文献>Molecular and Cellular Biology >Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function
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Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function

机译：Berardinelli-Seip先天性脂肪营养不良2 / Seipin不是棕色脂肪形成所必需的但它调节棕色脂肪组织的发育和功能

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Brown adipose tissue (BAT) plays a unique role in regulating whole-body energy homeostasis by dissipating energy through thermogenic uncoupling. Berardinelli-Seip congenital lipodystrophy (BSCL) type 2 (BSCL2; also known as seipin) is a lipodystrophy-associated endoplasmic reticulum membrane protein essential for white adipocyte differentiation. Whether BSCL2 directly participates in brown adipocyte differentiation, development, and function, however, is unknown. We show that BSCL2 expression is increased during brown adipocyte differentiation. Its deletion does not impair the classic brown adipogenic program but rather induces premature activation of differentiating brown adipocytes through cyclic AMP (cAMP)/protein kinase A (PKA)-mediated lipolysis and fatty acid and glucose oxidation, as well as uncoupling. cAMP/PKA signaling is physiologically activated during neonatal BAT development in wild-type mice and greatly potentiated in mice with genetic deletion of Bscl2 in brown progenitor cells, leading to reduced BAT mass and lipid content during neonatal brown fat formation. However, prolonged overactivation of cAMP/PKA signaling during BAT development ultimately causes apoptosis of brown adipocytes through inflammation, resulting in BAT atrophy and increased overall adiposity in adult mice. These findings reveal a key cell-autonomous role for BSCL2 in controlling BAT mass/activity and provide novel insights into therapeutic strategies targeting cAMP/PKA signaling to regulate brown adipocyte function, viability, and metabolic homeostasis.
机译：棕色脂肪组织（BAT）在通过热解耦耗散能量来调节全身能量稳态中起着独特的作用。 Berardinelli-Seip 2型先天性脂肪营养不良（BSCL）2型（BSCL2；也称为seipin）是与脂肪营养不良相关的内质网膜蛋白，对白色脂肪细胞的分化至关重要。尚不清楚BSCL2是否直接参与褐色脂肪细胞的分化，发育和功能。我们显示棕色脂肪细胞分化过程中增加BSCL2表达。它的缺失不会损害经典的棕色脂肪形成程序，而是通过环AMP（cAMP）/蛋白激酶A（PKA）介导的脂解作用，脂肪酸和葡萄糖氧化以及解偶联作用，诱导分化的棕色脂肪细胞过早激活。 cAMP / PKA信号传导在野生型小鼠的新生儿BAT发育过程中被生理激活，并且在棕色祖细胞中具有Bscl2基因缺失的小鼠中大大增强，从而导致新生儿棕色脂肪形成过程中BAT质量和脂质含量降低。但是，BAT产生过程中cAMP / PKA信号的过度过度活化最终会通过炎症导致褐色脂肪细胞凋亡，从而导致BAT萎缩和成年小鼠整体肥胖增加。这些发现揭示了BSCL2在控制BAT质量/活性中的关键的细胞自主作用，并为靶向cAMP / PKA信号传导调节棕色脂肪细胞功能，生存力和代谢稳态的治疗策略提供了新见解。

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