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The Role of Short-Chain Fatty Acid Sensing in Regulating Hepatic Glucose Production

短链脂肪酸传感在调节肝葡萄糖产生中的作用

基本信息

批准号：
10624981
负责人：
Frank Anthony Duca
金额：
$ 37.52万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10624981
关键词：
Acetates Affect Automobile Driving Blood Glucose Body Weight Body Weight decreased Brain Butyrates Characteristics Chronic Closure by clamp Collection Colon Consumption Coupled Data Development Diabetes Mellitus Dietary Intervention Distal Eating Economic Burden Epidemic Epigenetic Process FFAR2 gene FOXO1A gene Fatty acid glycerol esters Fermentation Fiber Food Fructans Gastrointestinal tract structure Gene Expression Genetic Transcription Gluconeogenesis Glucose Glucose tolerance test Goals HDAC5 gene Hepatic High Fat Diet Histone Deacetylase Histone Deacetylase Inhibitor Hyperglycemia Incidence Infusion procedures Intestines Inulin Large Intestine Life Style Liver Maintenance Mediating Metabolic Microbe Neurons Non-Insulin-Dependent Diabetes Mellitus Operative Surgical Procedures Pancreas Pathway interactions Peripheral Pharmacological Treatment Play Portal vein structure Prevalence Production Propionates Rattus Regulation Research Role Signal Pathway Signal Transduction Site Small Intestines Techniques Testing Therapeutic United States Viral Volatile Fatty Acids Work blood glucose regulation detection of nutrient dietary effective therapy feeding glucose production glucose tolerance gut microbes gut microbiota hepatic gluconeogenesis improved in vivo in vivo Model inhibitor insight knock-down microbiota novel overexpression prebiotics social targeted treatment transcription factor

项目摘要

The prevalence of diabetes continues to rise unabated in the United States, creating a grave social and economic burden. Current pharmacological treatments are only moderately effective at lowering glycemia, while metabolic surgery is effective, yet highly invasive. Interestingly, both therapeutic options alter the gut microbiota, the collection of all the microbes residing in the gastrointestinal tract, highlighting the role of gut microbes in the development and amelioration of diabetes. The long-term goal of this project is to better understand the mechanisms of the gut microbiota impacting glucose homeostasis. Prebiotics represent one of the more promising dietary strategies to alter the gut microbiota composition and improve metabolic dysregulation. Treatment with oligofructose (OFS), a non-digestible fiber, lowers blood glucose levels, improves glucose tolerance, and increases production of short-chain fatty acids (SCFAs) in the distal intestine. As such, SCFA treatment also results in metabolic benefits, including weight loss and improved glucose tolerance. Despite this, how SCFAs improves glucose homeostasis, and whether these mechanisms are required for the beneficial effects of prebiotics, remains unknown. For example, small intestinal propionate infusion activates a gut-brain-liver axis to lower hepatic glucose production, but whether this pathway exists in the colon, where the majority of SCFAs are produced, is unknown. Furthermore, SCFAs can enter the portal vein and act on the liver, but their role in hepatic glucose regulation is not clear. Interestingly, butyrate and propionate can act as epigenetic regulators, inhibiting histone deacetylases (HDACs), but it is unknown whether SCFAs affect downstream hepatic transcription factors that directly regulate hepatic gluconeogenesis. This, with our preliminary data, led to the hypothesis that SCFAs improve glucose tolerance by directly and indirectly targeting hepatic glucose production (HGP), both pathways of which are responsible for mediating the beneficial effects of OFS treatment. By utilizing sophisticated in-vivo surgical and viral manipulations during glucose tolerance tests or pancreatic clamps, this hypothesis will be tested in 3 aims: 1) determine if preabsorptive SCFAs activates a colonic-brain-liver axis to lower HGP, 2) examine the ability of portal SCFAs to inhibit HDAC activity to lower HGP, and 3) determine if gut-brain-liver axis signaling or hepatic HDAC inhibition are responsible for the glucoregulatory benefits of prebiotics due to increased SCFAs. A better understanding of how prebiotics and SCFAs improve glucose homeostasis could lead to targeted therapies that reduce chronically elevated HGP during diabetes.

在美国，糖尿病的患病率有增无减，社会和经济负担。目前的药物治疗只有适度有效降低血糖，而代谢手术是有效的，但高度侵入性。有趣的是，这两种治疗方案都改变了肠道微生物群，即所有肠道微生物的集合。微生物驻留在胃肠道，强调肠道微生物的作用，糖尿病的发展和改善。该项目的长期目标是更好地了解肠道微生物群影响葡萄糖稳态的机制。益生元代表了一个更有前途的饮食策略，以改变肠道微生物群组成和改善代谢失调。低聚果糖治疗 (OFS)，一种不易消化的纤维，降低血糖水平，改善葡萄糖耐量，增加远端肠道中短链脂肪酸（SCFA）的产生。因此，SCFA 治疗也会带来代谢方面的益处，包括体重减轻和血糖改善。宽容尽管如此，SCFAs如何改善葡萄糖稳态，以及这些益生元的有益作用所需的机制仍然未知。为例如，小肠丙酸盐输注激活肠-脑-肝轴，以降低肝细胞的存活率。葡萄糖的生产，但这种途径是否存在于结肠，其中大多数SCFAs 生产出来的，是未知的。此外，SCFAs可以进入门静脉并作用于肝脏，但它们在肝脏葡萄糖调节中的作用尚不清楚。有趣的是，丁酸和丙酸可以作为表观遗传调节剂，抑制组蛋白脱乙酰酶（HDAC），但它是未知的 SCFAs是否影响直接调节肝脏的下游肝脏转录因子异源发生根据我们的初步数据，这导致了SCFAs改善通过直接和间接靶向肝葡萄糖生成（HGP），其途径负责介导OFS治疗的有益效果。通过在葡萄糖耐量试验期间利用复杂的体内手术和病毒操作，或胰腺钳，将在3个目的中检验该假设：1）确定预吸收SCFA是否激活结肠-脑-肝轴以降低HGP，2）检查门静脉SCFAs抑制HGP的能力， HDAC活性以降低HGP，和3）确定肠-脑-肝轴信号传导或肝HDAC是否由于SCFA增加，益生元的葡萄糖调节益处是由抑制作用引起的。更好地了解益生元和SCFAs如何改善葡萄糖稳态可能会导致到靶向治疗，减少慢性升高的HGP在糖尿病。