Dietary, energy balance, and behavioural factors affecting postprandial fructose metabolism and the impact on normal glucose and lipid metabolism.

自20世纪70年代以来，加拿大人的膳食果糖摄入量显著增加，并在过去十年中一直保持在高位。膳食果糖来源主要包括加工或工业制备的食品，果糖（如甘蔗和甜菜糖或高果糖玉米糖浆）是一种主要的全球商品，对北美农业和食品工业（如高果糖玉米糖浆）尤其重要。然而，大多数关于哺乳动物体内果糖代谢的已知信息都是在没有使用生理相关的长期摄入量或短期极高摄入量的研究中报告的。我们需要对果糖的代谢，特别是餐后的代谢，有一个更好的生物学和生理学的基础认识。本项目将使用两种动物模型和稳定同位素技术来更好地了解餐后果糖代谢与正常葡萄糖和脂质代谢之间的关系。首先，本项目将使用高果糖喂养C57BL/6J小鼠模型来验证长期暴露和增加果糖摄入会失调餐后葡萄糖和脂质代谢，并产生肝脏含量增加、胰岛素抵抗和异常脂质运输的表型。将对小鼠进行进一步的研究，以确定性别、能量平衡和运动训练在果糖餐后代谢中的作用。其次，采用多导管猪模型（即尤卡坦微型猪，与人类胃肠道高度同源的成熟模型），本项目将研究餐后期间果糖在特定器官（如小肠、肝脏和外周组织）内和之间的代谢情况。小肠和肝脏在果糖、葡萄糖和脂类的代谢中起着关键作用。因此，了解这些组织如何随着餐后摄入的增加而代谢果糖，对于理解果糖如何影响正常的葡萄糖和脂质代谢至关重要。这组实验（超过5年的NSERC DG周期）将通过饮食（如高热量梯度和低热量梯度）和运动训练（如电动跑步机）在有和没有高果糖喂养的情况下仔细操纵能量平衡。生理（如间接量热、体重增加、身体组成）、生化（如血糖、脂质、胰岛素）和功能（如通过稳定同位素生成脂肪）数据将被收集和分析，以确定果糖对肝脏脂质代谢失调和相关表型的相对贡献。

Dietary fructose intakes of Canadians have significantly increased since the 1970s and have remained consistently high for the last decade. Dietary fructose sources mainly include processed or industrially prepared foods and fructose (e.g. cane and beet sugar or high fructose corn syrup) is a major worldwide commodity particularly important to the North American agricultural and food industries (i.e. high fructose corn syrup). However, most of what is known about the metabolism of fructose in mammals are reported in studies not using physiologically relevant long-term intakes or short-term extremely high amounts. A better basic biological and physiological understanding of fructose metabolism, particularly in the postprandial period is needed. This program of study will use two animal models and stable isotope techniques to better understand the relationship between postprandial fructose metabolism and normal glucose and lipid metabolism. Firstly, using high fructose feeding C57BL/6J mouse model this program will test the hypothesis that long-term exposure and increasing fructose intake dysregulates postprandial glucose and lipid metabolism and produces a phenotype of increased hepatic liver content, insulin resistance and aberrant lipid trafficking. Additional studies in mice will be conducted to determine the role sex, energy balance and exercise training play in the postprandial metabolism of fructose. Secondly, using a multiple catheterization pig model (i.e. Yucatan miniature pig, well-established model with high degree of gastrointestinal tract homology with humans) this program will study how fructose is metabolized in and between specific organs (i.e. small intestine, liver, and peripheral tissues) during the postprandial period. The small intestine and liver play pivotal roles in the metabolism of fructose, as well as glucose and lipids. Therefore, characterizing how these tissues metabolize fructose with increasing intake in the postprandial period is critical to understanding how fructose impact normal glucose and lipid metabolism. This set of experiments (over 5 year NSERC DG cycle) will carefully manipulate energy balance through diet (e.g. hyper and hypocaloric gradient), and exercise training (e.g. motorized treadmill) with and without high fructose feeding. Physiological (e.g. indirect calorimetry, weight gain, body composition), biochemical (e.g. blood glucose, lipids, insulin) and functional (e.g. lipogenesis by stable isotope) data will be collected and analyzed to determine the relative contribution of fructose to dysregulation of hepatic lipid metabolism and the related phenotype.