The role of PKM2 in dietary lipid absorption and fructose-induced obesity

在过去的五十年里，肥胖症的日益流行已经被热量甜味剂消费的增加所掩盖。所有最常见的热量甜味剂都含有相当大比例的果糖，包括蔗糖、蜂蜜和高果糖玉米糖浆（HFCS）。虽然果糖可能自人类开始以来就一直是饮食的一部分，但西方世界的人类现在消耗的果糖比以往任何时候都多。我们必须了解果糖如何影响我们的身体，并开发新的治疗策略以预防其并发症。我们和其他人已经表明，每日适度暴露于膳食果糖会加剧高脂肪饮食的致肥胖作用，但这种情况发生的机制仍不确定。我们的初步数据确定绒毛肥大和增强脂质摄取的小鼠喂养的饮食含有蔗糖或HFCS。肠上皮细胞的代谢组学和生化分析表明，果糖1-磷酸（F1 P），主要的果糖代谢产物，增加后饮食果糖和降低丙酮酸激酶（PK）的活性。PK的遗传和药理学激活减少绒毛长度并防止饮食诱导的体重增加。因此，我们假设果糖通过作为肠上皮细胞中PK的M2同工酶（PKM 2）的抑制剂促进绒毛肥大和脂质摄取，这可以用PK激活剂预防和逆转。我们将在小鼠和肠道类器官中使用饮食和药物干预来验证这一假设。在目标1中，我们将在小鼠肠道中对酮己糖激酶（从果糖产生F1 P的酶）和PKM 2进行遗传和非遗传操作，以询问它们作为饮食诱导的肥胖症的介导者的作用。在目标2中，我们将定义PK活性对肠细胞脂质代谢的影响，以阐明膳食果糖和肥胖之间的机制联系。总之，这些目标将改变我们对果糖如何改变肠道代谢的基本理解，将果糖/F1 P/PKM 2轴定义为脂质摄取的代谢介质，并为PKM 2激活剂作为对抗肥胖的新型治疗方式提供临床前证据。

The increasing prevalence of obesity has been paralleled by a rise in the consumption of caloric sweeteners over the past five decades. All of the most common caloric sweeteners contain a significant proportion of fructose, including table sugar (sucrose), honey, and high-fructose corn syrup (HFCS). Although fructose has likely been part of the diet since the beginning of mankind, humans in the western world now consume more than ever recorded. It is imperative that we understand how fructose impacts our bodies and develop novel treatment strategies to prevent its complications. We and others have shown that moderate daily exposure to dietary fructose exacerbates the obesogenic effects of a high fat diet, however the mechanisms by which this occurs remain uncertain. Our preliminary data identify villous hypertrophy and enhanced lipid uptake in mice fed diets containing sucrose or HFCS. A metabolomic and biochemical analysis of the intestinal epithelium show that fructose 1-phosphate (F1P), the primary fructose metabolite, is increased after dietary fructose and reduces pyruvate kinase (PK) activity. Genetic and pharmacologic activation of PK reduces villous length and protects against diet-induced weight gain. Therefore, we hypothesize that fructose promotes villous hypertrophy and lipid uptake by acting as an inhibitor of the M2 isozyme of PK (PKM2) in the enterocyte, which can be prevented and reversed with PK activators. We will test this hypothesis using dietary and pharmacologic interventions in mice and intestinal organoids. In Aim 1, we will genetically and pharmacologically manipulate ketohexokinase, the enzyme that produces F1P from fructose, and PKM2 in the intestines of mice to interrogate their role as mediators of diet-induced obesity. In Aim 2, we will define the effects of PK activity on enterocyte lipid metabolism to elucidate the mechanistic link between dietary fructose and obesity. Together, these aims will change our fundamental understanding of how fructose alters intestinal metabolism, define the fructose/F1P/PKM2 axis as a metabolic mediator of lipid uptake, and provide pre-clinical evidence for PKM2 activators as a novel therapeutic modality to combat obesity.