Developmental alterations of intestinal SGLT1 and GLUT2 induced by early weaning coincides with persistent low-grade metabolic inflammation in female pigs
Developmental alterations of intestinal SGLT1 and GLUT2 induced by early weaning coincides with persistent low-grade metabolic inflammation in female pigs
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DOI：
10.1152/ajpgi.00207.2021
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发表时间：
2022-03-01
影响因子：
4.5
通讯作者：
Moeser, Adam J.
中科院分区：
文献类型：
--
作者：
Li, Yihang;Thelen, Kyan M.;Moeser, Adam J.
早期生活逆境（ELA）与晚年炎症和代谢疾病的风险增加有关，但其机制仍知之甚少。肠上皮葡萄糖转运蛋白钠-葡萄糖连接转运蛋白1（SGLT 1）和葡萄糖转运蛋白2（GLUT 2）是肠葡萄糖摄取的主要途径，但作为炎症和代谢疾病的调节剂也受到越来越多的关注。在这里，我们测试的假设，早期断奶（EW）在猪，ELA的一个既定的模型，改变上皮葡萄糖转运蛋白的发展，并符合代谢性炎症的标志物升高。90日龄断奶仔猪（断奶16日龄）空肠和回肠SGLT 1活性较晚断奶仔猪（断奶28日龄）对照组降低约30%（P < 0.05）。与此相反，GLUT 2介导的葡萄糖转运增加（P = 0.003）在EW猪比LW猪。SGLT 1和GLUT 2介导的转运的相互变化与在90天和150日龄时观察到的肠刷状缘膜（BBM）中的转运蛋白表达一致。在EW和LW猪中，回肠SGLT 1介导的葡萄糖转运和BBM表达受到P-肾上腺素能受体（β AR）阻滞剂普萘洛尔的抑制。与此相反，普萘洛尔增强回肠GLUT 2介导的葡萄糖转运（P = 0.015）和刷状缘膜囊泡（BBMV）丰度（P = 0.035）在LW猪，但不是在EW猪。早期断奶仔猪表现出慢性血糖和C-反应蛋白（CRP）水平升高，脂肪细胞肥大和内脏脂肪组织中脂肪生成相关基因表达上调。EW改变肠道葡萄糖转运蛋白的发展可能会增加日后炎症和代谢性疾病的风险。新&值得注意的是这些研究表明，早期生活逆境的形式早期断奶的猪导致发展转变肠道葡萄糖转运从SGLT 1到GLUT 2介导的运输。早期断奶还诱导了代谢性炎症的标志物，包括血糖和炎症标志物CRP的持续升高，沿着内脏脂肪增多。肠道葡萄糖转运的改变可能会增加与早期生活逆境相关的炎症和代谢性疾病的风险。新&值得注意这些研究表明，猪早期断奶形式的早期生活逆境导致肠道葡萄糖转运从SGLT 1向GLUT 2介导的转运发生发育转变。早期断奶还诱导了代谢性炎症的标志物，包括血糖和炎症标志物CRP的持续升高，沿着内脏脂肪增多。肠道葡萄糖转运的改变可能会增加与早期生活逆境相关的炎症和代谢疾病的风险。
Early-life adversity (ELA) is linked with the increased risk for inflammatory and metabolic diseases in later life, but the mechanisms remain poorly understood. Intestinal epithelial glucose transporters sodium-glucose-linked transporter 1 (SGLT1) and glucose transporter 2 (GLUT2) are the major route for intestinal glucose uptake but have also received increased attention as modulators of inflammatory and metabolic diseases. Here, we tested the hypothesis that early weaning (EW) in pigs, an established model of ELA, alters the development of epithelial glucose transporters and coincides with elevated markers of metabolic inflammation. The jejunum and ileum of 90-day-old pigs previously exposed to EW (16 days wean age), exhibited reduced SGLT1 activity (by similar to 30%, P < 0.05) than late weaned (LW, 28 days wean age) controls. In contrast, GLUT2-mediated glucose transport was increased (P = 0.003) in EW pigs than in LW pigs. Reciprocal changes in SGLT1- and GLUT2-mediated transport coincided with transporter protein expression in the intestinal brush-border membranes (BBMs) that were observed at 90 days and 150 days of age. Ileal SGLT1-mediated glucose transport and BBM expression were inhibited by the P-adrenergic receptor (beta AR) blocker propranolol in EW and LW pigs. In contrast, propranolol enhanced ileal GLUT2-mediated glucose transport (P = 0.015) and brush-border membrane vesicle (BBMV) abundance (P = 0.035) in LW pigs, but not in EW pigs. Early-weaned pigs exhibited chronically elevated blood glucose and C-reactive protein (CRP) levels, and adipocyte hypertrophy and upregulated adipogenesis-related gene expression in visceral adipose tissue. Altered development of intestinal glucose transporters by EW could underlie the increased risk for later life inflammatory and metabolic diseases.NEW & NOTEWORTHY These studies reveal that early-life adversity in the form of early weaning in pigs causes a developmental shift in intestinal glucose transport from SGLT1 toward GLUT2-mediated transport. Early weaning also induced markers of metabolic inflammation including persistent elevations in blood glucose and the inflammatory marker CRP, along with increased visceral adiposity. Altered intestinal glucose transport might contribute to increased risk for inflammatory and metabolic diseases associated with early-life adversity.NEW & NOTEWORTHY These studies reveal that early-life adversity in the form of early weaning in pigs causes a developmental shift in intestinal glucose transport from SGLT1 toward GLUT2-mediated transport. Early weaning also induced markers of metabolic inflammation including persistent elevations in blood glucose and the inflammatory marker CRP, along with increased visceral adiposity. Altered intestinal glucose transport might contribute to increased risk for inflammatory and metabolic diseases associated with early-life adversity.