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，糖尿病的患病率继续升高，创造了一个坟墓社会和经济负担。当前的药理治疗仅适度有效地降低糖血症，而代谢手术则有效，但具有高度侵入性。有趣的是，两种治疗选择都会改变肠道微生物群，收集所有居住在胃肠道中的微生物，突出了肠道微生物在糖尿病的发展和改善。该项目的长期目标是改善了解影响葡萄糖稳态的肠道菌群的机制。益生元代表了改变肠道的最有前途的饮食策略之一菌群组成并改善代谢失调。用寡聚果糖处理（OFS），一种不可消化的纤维，可降低血糖水平，提高葡萄糖耐受性，并增加远端肠中短链脂肪酸（SCFA）的产生。因此，SCFA 治疗还会导致代谢益处，包括体重减轻和葡萄糖改善宽容。尽管如此，SCFA如何改善葡萄糖稳态，以及这些是否是否益生元的有益作用所必需的机制仍然未知。为了例如，小肠pp次输注激活肠道肝轴以降低肝葡萄糖产生，但是该途径是否存在于大多数SCFA的结肠中是生产的，是未知的。此外，SCFA可以进入门户静脉并在肝脏上起作用，但是它们在肝葡萄糖调节中的作用尚不清楚。有趣的是，丁酸酯和丙酸可以充当表观遗传调节剂，抑制组蛋白脱乙酰基酶（HDAC），但未知 SCFA是否影响直接调节肝的下游肝转录因子糖异生。通过我们的初步数据，这导致了SCFA改善的假设通过直接和间接靶向肝葡萄糖产生（HGP），葡萄糖耐受性，两者都其途径负责介导OFS治疗的有益作用。经过在葡萄糖耐受性测试期间使用复杂的体内手术和病毒操纵或胰腺夹具，该假设将以3个目的进行检验：1）确定是否有刺激性SCFA 激活结肠脑肝轴以降低HGP，2）检查门户SCFA抑制的能力 HGP降低HGP的HDAC活性，3）确定肠道肝轴信号传导或肝HDAC是抑制作用是由于SCFA增加而导致益生元的葡萄糖调节益处。更好地理解益生元和SCFA如何改善葡萄糖稳态可能会导致针对降低糖尿病期间长期升高HGP的靶向疗法。