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

PKM2 在膳食脂质吸收和果​​糖诱导的肥胖中的作用

• 批准号: 10612965
• 负责人: Marcus DaSilva Goncalves
• 金额: $ 55.92万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10612965
• 关键词: Address; Adult; Affect; Biochemical; Calories; Cell Proliferation; Cell Survival; Cessation of life; Chylomicrons; Consumption; Cost of Illness; Data; Diet; Dietary Fats; Dietary Sucrose; Eating; Energy Metabolism; Enterocytes; Enzymes; Exercise; Exposure to; Fatty acid glycerol esters; Feces; Fructose; Genetic; Genetic Models; Glucose Intolerance; Goals; Heart Diseases; High Fat Diet; Honey; Human; Hyperinsulinism; Hyperplasia; Hypertrophy; Intervention; Intestines; Isoenzymes; Isotopes; Ketohexokinase; Length; Link; Lipids; Lipoproteins; Liver; Mass Spectrum Analysis; Measures; Mediator; Metabolic; Metabolism; Modality; Morbid Obesity; Mus; Nature; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Obesity; Obesity Epidemic; Organoids; Physical activity; Play; Prevalence; Prospective Studies; Protein Isoforms; Pyruvate Kinase; Research; Risk; Role; Science; Small Intestines; Stroke; Sucrose; Sweetening Agents; Testing; Time; Tracer; Triglycerides; Villous; Villus; Weight Gain; Western World; Wild Type Mouse; Work; absorption; cancer type; cell motility; clinical development; combat; diet-induced obesity; dietary; dietary restriction; experimental study; fructose-1-phosphate; improved; inhibitor; intestinal epithelium; lipid biosynthesis; lipid mediator; lipid metabolism; lipid transport; metabolomics; novel; novel therapeutics; nutrient absorption; obese patients; obesity prevention; obesity risk; obesity treatment; obesogenic; pharmacologic; pre-clinical; premature; prevent; response; small molecule; sugar; treatment strategy; uptake

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.

在过去的50年里，随着肥胖的日益流行，高热量甜味剂的消费量也在增加。所有最常见的高热量甜味剂都含有大量的果糖，包括蔗糖、蜂蜜和高果糖玉米糖浆。尽管果糖可能从人类诞生之初就已经成为饮食的一部分，但西方世界的人类现在消耗的果糖比以往任何时候都要多。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来预防其并发症。我们和其他人已经表明，每日适量摄入果糖会加剧高脂肪饮食的致肥作用，但其发生的机制仍不确定。我们的初步数据表明，在喂食含有蔗糖或高果糖玉米糖浆的饲料的小鼠中，绒毛肥大和脂质摄取增强。肠道上皮代谢组学和生化分析表明，果糖的主要代谢物果糖1-磷酸（F1P）在摄入果糖后增加，并降低丙酮酸激酶（PK）活性。遗传和药理学激活的PK减少绒毛长度和防止饮食引起的体重增加。因此，我们假设果糖通过作为肠细胞中PK的M2同工酶（PKM2）的抑制剂来促进绒毛肥大和脂质摄取，这可以通过PK激活剂来预防和逆转。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Aim 1中，我们将从遗传和药理学上操纵小鼠肠道中的酮己糖激酶（一种从果糖中产生F1P的酶）和PKM2，以探究它们作为饮食诱导肥胖介质的作用。在Aim 2中，我们将定义PK活性对肠细胞脂质代谢的影响，以阐明膳食果糖与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/F1P/PKM2轴定义为脂质摄取的代谢介质，并为PKM2激活剂作为对抗肥胖的新治疗方式提供临床前证据。