Department of Obstetrics and Gynecology, Baylor College of Medicine , Houston, Texas.
Department of Surgery, Houston Methodist Hospital Research Institute , Houston, Texas.
Am J Physiol Endocrinol Metab. 2018 Dec 1;315(6):E1251-E1263. doi: 10.1152/ajpendo.00001.2018. Epub 2018 Aug 14.
Pancreatic β-cell expansion is a highly regulated metabolic adaptation to increased somatic demands, including obesity and pregnancy; adult β cells otherwise rarely proliferate. We previously showed that high-fat diet (HFD) feeding induces mouse β-cell proliferation in less than 1 wk in the absence of insulin resistance. Here we metabolically profiled tissues from a short-term HFD β-cell expansion mouse model to identify pathways and metabolite changes associated with β-cell proliferation. Mice fed HFD vs. chow diet (CD) showed a 14.3% increase in body weight after 7 days; β-cell proliferation increased 1.75-fold without insulin resistance. Plasma from 1-wk HFD-fed mice induced β-cell proliferation ex vivo. The plasma, as well as liver, skeletal muscle, and bone, were assessed by LC and GC mass-spectrometry for global metabolite changes. Of the 1,283 metabolites detected, 159 showed significant changes [false discovery rate (FDR) < 0.1]. The majority of changes were in liver and muscle. Pathway enrichment analysis revealed key metabolic changes in steroid synthesis and lipid metabolism, including free fatty acids and other bioactive lipids. Other important enrichments included changes in the citric acid cycle and 1-carbon metabolism pathways implicated in DNA methylation. Although the minority of changes were observed in bone and plasma (<20), increased p-cresol sulfate was increased >4 fold in plasma (the largest increase in all tissues), and pantothenate (vitamin B) decreased >2-fold. The results suggest that HFD-mediated β-cell expansion is associated with complex, global metabolite changes. The finding could be a significant insight into Type 2 diabetes pathogenesis and potential novel drug targets.
胰岛β细胞的扩增是一种高度受调节的代谢适应，以满足包括肥胖和妊娠在内的机体需求增加；成年β细胞通常很少增殖。我们之前曾表明，高脂肪饮食（HFD）喂养可在不到 1 周的时间内诱导小鼠β细胞增殖，而不会引起胰岛素抵抗。在此，我们对短期高脂肪饮食β细胞扩增小鼠模型的组织进行了代谢分析，以确定与β细胞增殖相关的途径和代谢物变化。与喂食标准饮食（CD）的小鼠相比，喂食 HFD 的小鼠在 7 天后体重增加了 14.3％；β细胞增殖增加了 1.75 倍，而没有胰岛素抵抗。喂食 HFD 1 周的小鼠的血浆在体外可诱导β细胞增殖。通过 LC 和 GC 质谱对血浆以及肝脏、骨骼肌和骨骼进行了全面代谢物变化的评估。在所检测到的 1283 种代谢物中，有 159 种显示出显著变化[错误发现率（FDR）<0.1]。大多数变化发生在肝脏和肌肉中。途径富集分析显示，类固醇合成和脂质代谢中的关键代谢变化，包括游离脂肪酸和其他生物活性脂质。其他重要的富集途径包括柠檬酸循环和 1 碳代谢途径的变化，这些途径与 DNA 甲基化有关。尽管在骨骼和血浆中观察到的变化较少（<20），但血浆中的对羟基苯硫酸（p-cresol sulfate）增加了>4 倍（所有组织中增加最多），泛酸（维生素 B）减少了>2 倍。这些结果表明，HFD 介导的β细胞扩增与复杂的、全面的代谢物变化有关。这一发现可能为 2 型糖尿病发病机制和潜在的新型药物靶点提供重要的见解。
