Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice.
Lack of adipose-specific hexose-6-phosphate dehydrogenase causes inactivation of adipose glucocorticoids and improves metabolic phenotype in mice.
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缺乏脂肪特异性六磷酸己糖脱氢酶会导致脂肪糖皮质激素失活并改善小鼠的代谢表型。
DOI：
10.1042/cs20190679
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Liu,Yanjun
中科院分区：
文献类型：
--
作者：
Wang,Jian;Wang,Ying;Liu,Limei;Lutfy,Kabirullah;Friedman,TheodoreC;Liu,Ya;Jiang,Meisheng;Liu,Yanjun
脂肪组织中糖皮质激素（GC）的过量产生促进了内脏型肥胖和代谢综合征（MS）的发展。11β-羟基类固醇脱氢酶1（11β-hydroxysteroid dehydrogenase type 1，11β-HSD 1）是控制细胞内GC生成的关键酶，该过程受6-磷酸己糖脱氢酶（H6 PDH）的严格调控。为了更好地理解脂肪H6 PDH的综合分子生理效应，我们在脂肪细胞中建立了H6 PDH基因的组织特异性敲除小鼠模型（H6 PDH的脂肪细胞特异性条件性敲除（H6 PDHAc KO）小鼠）。H6 PDHAc KO小鼠表现出几乎完全缺乏H6 PDH表达，脂肪内皮质酮产生减少，脂肪组织中11β-HSD 1活性降低。这些小鼠的腹部脂肪量也减少，这是由于脂肪生成乙酰辅酶A羧化酶（ACC）和ATP-柠檬酸裂解酶（ACL）基因表达减少以及转录因子C/EBPα mRNA水平降低所致。此外，H6 PDHAc KO小鼠还具有降低的空腹血糖水平、增加的葡萄糖耐量和增加的胰岛素敏感性。此外，血浆游离脂肪酸（FFA）水平降低，伴随着脂肪组织中脂肪酶脂肪甘油三酯脂肪酶（ATGL）和脂肪敏感脂肪酶（HSL）表达的降低。这些结果表明，脂肪细胞H6 PDH表达的失活足以引起脂肪内GC失活，从而导致有利的代谢表型模式。这些数据表明，H6 PDHAc KO小鼠可能提供了一个很好的模型，用于研究脂肪特异性H6 PDH抑制对改善体内代谢表型的潜在贡献。我们的研究表明，抑制或失活脂肪细胞中的H6 PDH表达可能是治疗肥胖和糖尿病的有效干预措施。
Excessive glucocorticoid (GC) production in adipose tissue promotes the development of visceral obesity and metabolic syndrome (MS). 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) is critical for controlling intracellular GC production, and this process is tightly regulated by hexose-6-phosphate dehydrogenase (H6PDH). To better understand the integrated molecular physiological effects of adipose H6PDH, we created a tissue-specific knockout of the H6PDH gene mouse model in adipocytes (adipocyte-specific conditional knockout of H6PDH (H6PDHAcKO) mice). H6PDHAcKOmice exhibited almost complete absence of H6PDH expression and decreased intra-adipose corticosterone production with a reduction in 11β-HSD1 activity in adipose tissue. These mice also had decreased abdominal fat mass, which was paralleled by decreased adipose lipogenic acetyl-CoA carboxylase (ACC) and ATP-citrate lyase (ACL) gene expression and reduction in their transcription factor C/EBPα mRNA levels. Moreover, H6PDHAcKOmice also had reduced fasting blood glucose levels, increased glucose tolerance, and increased insulin sensitivity. In addition, plasma free fatty acid (FFA) levels were decreased with a concomitant decrease in the expression of lipase adipose triglyceride lipase (ATGL) and hormone-sensitive lipase (HSL) in adipose tissue. These results indicate that inactivation of adipocyte H6PDH expression is sufficient to cause intra-adipose GC inactivation that leads to a favorable pattern of metabolic phenotypes. These data suggest that H6PDHAcKOmice may provide a good model for studying the potential contributions of fat-specific H6PDH inhibition to improve the metabolic phenotypein vivo. Our study suggests that suppression or inactivation of H6PDH expression in adipocytes could be an effective intervention for treating obesity and diabetes.
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影响因子：
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