Enhanced hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to diet-induced visceral adiposity
Enhanced hexose-6-phosphate dehydrogenase expression in adipose tissue may contribute to diet-induced visceral adiposity
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脂肪组织中六磷酸己糖脱氢酶表达增强可能导致饮食引起的内脏肥胖
DOI：
10.1038/s41366-018-0041-1
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发表时间：
2018-12-01
影响因子：
4.9
通讯作者：
Liu, Yanjun
中科院分区：
文献类型：
--
作者：
Liu, Limei;Wang, Ying;Liu, Yanjun
背景技术背景：内脏脂肪堆积增加了发展2型糖尿病和代谢综合征的风险，并与过量的糖皮质激素（GC）有关。脂肪库特异性GC作用由11 SS-羟基类固醇脱氢酶（11 SS-HSD 1）与己糖-6-磷酸脱氢酶（H6 PDH）偶联严格控制。H6 PDH基因失活或激活的小鼠显示脂肪11 SS-HSD 1活性和脂质储存改变。我们推测脂肪组织H6 PDH活化是内脏型肥胖和胰岛素抵抗的主要原因。在此，我们探讨了在体内增加脂肪H6 PDH在内脏脂肪形成中的作用和可能的机制。我们通过内脏脂肪肥胖基因表达谱、脂肪分布、脂肪细胞代谢分子，和腹部脂肪特异性GC信号传导机制，这些机制是喂食标准高脂饮食（HFD）的H6 PDH转基因小鼠中饮食诱导的内脏肥胖和胰岛素抵抗的基础。转基因H6 PDH小鼠显示增加的腹部脂肪积累，这是由与脂肪组织内的脂肪生成转录子C/EBP α和PPAR γ mRNA水平的诱导相关的脂质合成升高引起的。与WT对照组相比，喂食高脂饮食（HFD）的转基因H6 PDH小鼠获得了更多的腹部内脏脂肪量，同时激活了GSK 3 β和诱导了XBP 1/IRE 1 α，但降低了内脏脂肪组织中的pThr（308）Akt/PKB含量和布朗宁基因CD 137和GLUT 4 mRNA水平。HFD喂养的H6 PDH转基因小鼠也表现出胰岛素敏感性受损和脂肪内GC水平升高，并诱导脂肪11 β-HSD 1。结论：这些数据首次提供了体内机制证据，表明脂肪H6 PDH激活通过增强11 β-HSD 1驱动的脂肪内GC作用对内脏脂肪分布、脂肪代谢和脂肪细胞功能产生不利的代谢影响。
BACKGROUND: Visceral fat accumulation increases the risk of developing type 2 diabetes and metabolic syndrome, and is associated with excessive glucocorticoids (GCs). Fat depot-specific GC action is tightly controlled by 11SS-hydroxysteroid dehydrogenase (11SS-HSD1) coupled with the enzyme hexose-6-phosphate dehydrogenase (H6PDH). Mice with inactivation or activation of H6PDH genes show altered adipose 11SS-HSD1 activity and lipid storage. We hypothesized that adipose tissue H6PDH activation is a leading cause for the visceral obesity and insulin resistance. Here, we explored the role and possible mechanism of enhancing adipose H6PDH in the development of visceral adiposity in vivo.METHODS: We investigated the potential contribution of adipose H6PDH activation to the accumulation of visceral fat by characterization of visceral fat obese gene expression profiles, fat distribution, adipocyte metabolic molecules, and abdominal fat-specific GC signaling mechanisms underlying the diet-induced visceral obesity and insulin resistance in H6PDH transgenic mice fed a standard of high-fat diet (HFD).RESULTS: Transgenic H6PDH mice display increased abdominal fat accumulation, which is paralleled by elevated lipid synthesis associated with induction of lipogenic transcriptor C/EBP alpha and PPAR gamma mRNA levels within adipose tissue. Transgenic H6PDH mice fed a high-fat diet (HFD) gained more abdominal visceral fat mass coupled with activation of GSK3 beta and induction of XBP1/IRE1 alpha, but reduced pThr(308) Akt/PKB content and browning gene CD137 and GLUT4 mRNA levels within the visceral adipose tissue than WT controls. HFD-fed H6PDH transgenic mice also had impaired insulin sensitivity and exhibited elevated levels of intra-adipose GCs with induction of adipose 11SS-HSD1.CONCLUSION: These data provide the first in vivo mechanistic evidence for the adverse metabolic effects of adipose H6PDH activation on visceral fat distribution, fat metabolism, and adipocyte function through enhancing 11 beta-HSD1-driven intra-adipose GC action.