Department of Cell Biology, Microbiology and Molecular Biology, University of South Florida, 4202 East Fowler Avenue, BSF 206, Tampa, Florida 33620, USA Department of Pediatrics, University of South Florida, 12901 Bruce B. Downs Boulevard, MDC 62, Tampa, Florida 33612, USA.
J Endocrinol. 2014 Jan 27;220(3):219-31. doi: 10.1530/JOE-13-0338. Print 2014 Mar.
PANcreatic-DERived factor (PANDER, FAM3B) is a novel protein that is highly expressed within the endocrine pancreas and to a lesser degree in other tissues. Under glucose stimulation, PANDER is co-secreted with insulin from the β-cell. Despite prior creation and characterization of acute hepatic PANDER animal models, the physiologic function remains to be elucidated from pancreas-secreted PANDER. To determine this, in this study, a transgenic mouse exclusively overexpressing PANDER from the endocrine pancreas was generated. PANDER was selectively expressed by the pancreatic-duodenal homeobox-1 (PDX1) promoter. The PANDER transgenic (PANTG) mice were metabolically and proteomically characterized to evaluate effects on glucose homeostasis, insulin sensitivity, and lipid metabolism. Fasting glucose, insulin and C-peptide levels were elevated in the PANTG compared with matched WT mice. Younger PANTG mice also displayed glucose intolerance in the absence of peripheral insulin sensitivity. Hyperinsulinemic-euglycemic clamp studies revealed that hepatic glucose production and insulin resistance were significantly increased in the PANTG with no difference in either glucose infusion rate or rate of disappearance. Fasting glucagon, corticosterones, resistin and leptin levels were also similar between PANTG and WT. Stable isotope labeling of amino acids in cell culture revealed increased gluconeogenic and lipogenic proteomic profiles within the liver of the PANTG with phosphoenol-pyruvate carboxykinase demonstrating a 3.5-fold increase in expression. This was matched with increased hepatic triglyceride content and decreased p-AMPK and p-acetyl coenzyme A carboxylase-1 signaling in the PANTG. Overall, our findings support a role of pancreatic β-cell-secreted PANDER in the regulation of hepatic insulin and lipogenenic signaling with subsequent impact on overall glycemia.
胰腺衍生因子（PANDER，FAM3B）是一种在胰岛内高度表达的新型蛋白，在其他组织中也有一定程度的表达。在葡萄糖刺激下，PANDER 与胰岛素一起从β细胞中共同分泌。尽管先前已经建立并表征了急性肝 PANDER 动物模型，但从胰腺分泌的 PANDER 中其生理功能仍有待阐明。为了确定这一点，在本研究中，生成了一种专门在内分泌胰腺中过表达 PANDER 的转基因小鼠。PANDER 由胰腺十二指肠同源盒-1（PDX1）启动子选择性表达。对 PANDER 转基因（PANTG）小鼠进行了代谢和蛋白质组学特征分析，以评估其对葡萄糖稳态、胰岛素敏感性和脂质代谢的影响。与匹配的 WT 小鼠相比，PANTG 小鼠的空腹血糖、胰岛素和 C 肽水平升高。年轻的 PANTG 小鼠在没有外周胰岛素敏感性的情况下也表现出葡萄糖不耐受。高胰岛素-正常血糖钳夹研究表明，PANTG 的肝葡萄糖产生和胰岛素抵抗显著增加，而葡萄糖输注率或葡萄糖消失率没有差异。PANTG 和 WT 之间的空腹胰高血糖素、皮质酮、抵抗素和瘦素水平也相似。细胞培养中氨基酸的稳定同位素标记显示，PANTG 肝脏中的糖异生和脂肪生成蛋白质组谱增加，磷酸烯醇丙酮酸羧激酶的表达增加了 3.5 倍。这与 PANTG 肝脏中甘油三酯含量增加、p-AMPK 和 p-乙酰辅酶 A 羧化酶-1 信号降低相匹配。总的来说，我们的研究结果支持胰腺β细胞分泌的 PANDER 在调节肝脏胰岛素和脂肪生成信号中的作用，随后对整体血糖产生影响。
