Glycerol kinase stimulates uncoupling protein 1 expression by regulating fatty acid metabolism in beige adipocytes
Glycerol kinase stimulates uncoupling protein 1 expression by regulating fatty acid metabolism in beige adipocytes
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DOI：
10.1074/jbc.ra119.011658
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发表时间：
2020-05-15
影响因子：
4.8
通讯作者：
Goto, Tsuyoshi
中科院分区：
文献类型：
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作者：
Iwase, Mari;Tokiwa, Soshi;Goto, Tsuyoshi
脂肪组织的布朗宁是由特定的刺激如冷暴露诱导的，并且由白色脂肪组织中产热的上调组成。最近，它已成为管理人类肥胖的一个有吸引力的目标。在这里，我们进行了全面的分析，以确定与小鼠脂肪组织中的布朗宁相关的基因。我们专注于甘油激酶（GYK），因为它的mRNA表达模式与解偶联蛋白1（UCP 1）高度相关，解偶联蛋白1调节脂肪细胞的产热能力。在腹股沟白色脂肪组织（iWAT）中，冷应激诱导的Ucp 1上调被体内Gyk敲低（KD）部分消除。一致地，Gyk KD抑制由用？肾上腺素能受体（？AR）激动剂异丙肾上腺素（Iso）在体外，并导致受损的解偶联呼吸。Gyk KD还抑制Iso和腺苷酸环化酶激活剂诱导的cAMP反应元件结合蛋白（CREB）的转录激活和磷酸化。然而，我们没有观察到cAMP类似物的这些作用。因此，Gyk KD与Iso诱导的cAMP产物有关。在Iso处理的Gyk KD脂肪细胞中，硬脂酰辅酶A去饱和酶1（SCD 1）上调，单不饱和脂肪酸如棕榈油酸（POA）积累。此外，SCD 1抑制剂治疗恢复Gyk KD诱导的Ucp 1下调和POA治疗下调异源激活Ucp 1。我们的研究结果表明，Gyk刺激Ucp 1的表达通过一种机制，部分依赖于？AR-cAMP-CREB通路和Gyk介导的脂肪酸代谢调节。
Browning of adipose tissue is induced by specific stimuli such as cold exposure and consists of up-regulation of thermogenesis in white adipose tissue. Recently, it has emerged as an attractive target for managing obesity in humans. Here, we performed a comprehensive analysis to identify genes associated with browning in murine adipose tissue. We focused on glycerol kinase (GYK) because its mRNA expression pattern is highly correlated with that of uncoupling protein 1 (UCP1), which regulates the thermogenic capacity of adipocytes. Cold exposure-induced Ucp1 up-regulation in inguinal white adipose tissue (iWAT) was partially abolished by Gyk knockdown (KD) in vivo. Consistently, the Gyk KD inhibited Ucp1 expression induced by treatment with the ?-adrenergic receptors (?AR) agonist isoproterenol (Iso) in vitro and resulted in impaired uncoupled respiration. Gyk KD also suppressed Iso- and adenylate cyclase activator-induced transcriptional activation and phosphorylation of the cAMP response element-binding protein (CREB). However, we did not observe these effects with a cAMP analog. Therefore Gyk KD related to Iso-induced cAMP products. In Iso-treated Gyk KD adipocytes, stearoyl-CoA desaturase 1 (SCD1) was up-regulated, and monounsaturated fatty acids such as palmitoleic acid (POA) accumulated. Moreover, a SCD1 inhibitor treatment recovered the Gyk KD-induced Ucp1 down-regulation and POA treatment down-regulated Iso-activated Ucp1. Our findings suggest that Gyk stimulates Ucp1 expression via a mechanism that partially depends on the ?AR-cAMP-CREB pathway and Gyk-mediated regulation of fatty acid metabolism.