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

基本信息

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
项目类别：
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

项目摘要

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.

在过去的五十年里，肥胖症患病率的不断上升与热量甜味剂消费量的增加同时发生。所有最常见的热量甜味剂都含有大量果糖，包括食糖（蔗糖）、蜂蜜和高果糖玉米糖浆 (HFCS)。尽管果糖很可能自人类诞生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要多。我们必须了解果糖如何影响我们的身体，并制定新的治疗策略来预防其并发症。我们和其他人已经证明，每天适量摄入膳食果糖会加剧高脂肪饮食的肥胖效应，但发生这种情况的机制仍不确定。我们的初步数据表明，喂食含有蔗糖或高果糖玉米糖浆的小鼠的绒毛肥大和脂质摄取增强。肠上皮的代谢组学和生化分析表明，果糖 1-磷酸 (F1P)（主要果糖代谢物）在摄入果糖后会增加，并会降低丙酮酸激酶 (PK) 活性。 PK 的遗传和药理学激活可减少绒毛长度并防止饮食引起的体重增加。因此，我们假设果糖通过充当肠上皮细胞中 PK M2 同工酶 (PKM2) 的抑制剂来促进绒毛肥大和脂质摄取，而这可以通过 PK 激活剂来预防和逆转。我们将通过对小鼠和肠道类器官的饮食和药物干预来检验这一假设。在目标 1 中，我们将从基因和药理学角度操纵酮己糖激酶（一种从果糖产生 F1P 的酶）和小鼠肠道中的 PKM2，以探究它们作为饮食诱导肥胖调节剂的作用。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型治疗方式提供临床前证据。