Survivin is essential for thermogenic program and metabolic homeostasis in mice.
Survivin is essential for thermogenic program and metabolic homeostasis in mice.
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DOI：
10.1016/j.molmet.2022.101446
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发表时间：
2022-04
影响因子：
8.1
通讯作者：
Yang Y
中科院分区：
文献类型：
--
作者：
Alimujiang M;Sun J;Chen S;Bai N;Chen S;Hu F;Ma J;Xu Y;Xu J;Ma X;Yang Y
Survivin是凋亡抑制因子家族的成员。我们以前的研究表明，生存素的表达可以强烈诱导长期，高脂饮食（HFD）暴露在体内。在体外胰岛素也可通过PI 3 K/mTOR信号通路诱导其表达。因此，我们假设在某些条件下，生存素的表达可能是脂肪细胞功能所必需的。在目前的研究中，我们的目的是进一步研究不同的营养刺激后，在成熟的脂肪细胞中的生存素表达的调节和生存素的作用，使用脂肪细胞特异性生存素基因敲除（SKO）小鼠。通过将survivinflox/flox小鼠与脂联素-Cre +/-小鼠杂交获得SKO小鼠。在普通饲料（CD）和HFD喂养条件下观察到总体代谢表型。检测小鼠冷暴露后的产热程序。分离腹股沟白色脂肪组织（iWAT）和棕色脂肪组织（BAT）间质血管组分细胞，体外诱导分化为成熟脂肪细胞，检测Survivin基因缺失对成熟脂肪细胞功能的影响。在体内和体外，短期营养应激可调节脂肪组织和脂肪细胞中Survivin的表达。在SKO小鼠中，BAT的出生后发育受损，这导致在喂食CD的24周龄小鼠中BAT质量急剧减少，产热蛋白Ucp 1的表达降低。HFD喂养后，SKO小鼠iWAT和BAT质量显著降低，导致肝脏异位脂质积聚，这与胰岛素抵抗和葡萄糖耐受不良有关。冷暴露后，SKO小鼠BAT和iWAT中产热基因和蛋白的表达显著降低，伴随着线粒体结构异常和诱导的自噬。存活素缺失的棕色和米色脂肪细胞在体外培养时，产热程序和线粒体氧化磷酸化均减少。我们的研究结果表明，生存素可以在脂肪细胞的营养应激调节，并揭示了一个新的作用，生存素在维持正常的BAT质量和积极调节产热程序和线粒体氧化磷酸化。脂肪细胞中Survivin的表达受营养应激的调节。存活素是维持小鼠BAT质量和产热程序所必需的。当暴露于HFD时，脂肪细胞中的存活素缺失损害葡萄糖稳态。存活素是激活冷暴露的生热程序反应所必需的。脂肪细胞特异性生存素缺失在体内和体外诱导自噬。
Survivin is a member of the inhibitor of apoptosis family. Our previous study showed that survivin expression could be strongly induced by long-term, high-fat diet (HFD) exposure in vivo. It could also be induced by insulin through the PI3K/mTOR signaling pathway in vitro. Therefore, we hypothesized that under certain conditions, survivin expression might be required for adipocyte function. In the current study, we aim to further investigate the regulation of survivin expression in mature adipocytes upon various nutritional stimuli and the role of survivin using adipocyte-specific survivin knockout (SKO) mice. SKO mice were obtained by crossing survivinflox/flox mice with Adiponectin-Cre+/- mice. The overall metabolic phenotype was observed under chow diet (CD) and HFD feeding conditions. The thermogenic program of mice was detected upon cold exposure. The inguinal white adipose tissue (iWAT) and brown adipose tissue (BAT) stromal vascular fraction cells were isolated and differentiated into mature adipocytes, and the effects of survivin deletion on mature adipocyte function were detected in vitro. Survivin expression in adipose tissue and adipocytes was regulated by short-term nutritional stress both in vivo and in vitro. The postnatal development of BAT was impaired in SKO mice, which resulted in drastically reduced BAT mass and decreased expression of the thermogenic protein Ucp1 in 24-week-old mice fed with CD. After HFD feeding, the iWAT and BAT mass of SKO mice were significantly decreased, causing ectopic lipid accumulation in the liver, which was associated with insulin resistance and glucose intolerance. Upon cold exposure, the expression of thermogenic genes and proteins was markedly reduced in BAT and iWAT of SKO mice, accompanied by abnormal mitochondrial structure and induced autophagy. Consistently, thermogenic program and mitochondrial oxidative phosphorylation were reduced in survivin-depleted brown and beige adipocytes in vitro. Our findings showed that survivin could be regulated by nutritional stress in adipocytes and revealed a new role of survivin in maintaining normal BAT mass and positively regulating the thermogenic program and mitochondrial oxidative phosphorylation. Survivin expression in adipocytes is regulated by nutritional stress. Survivin is required for maintaining BAT mass and thermogenic program in mice. Survivin deletion in adipocytes impairs glucose homeostasis when exposed to HFD. Survivin is required for activation of thermogenic program response to cold exposure. Adipocyte-specific deletion of survivin induces autophagy in vivo and in vitro.
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