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有增无减，造成了严重的后果社会和经济负担。目前的药物治疗只能起到中等程度的作用可以有效降低血糖，而代谢手术虽然有效，但具有高度侵入性。有趣的是，这两种治疗选择都会改变肠道微生物群，即所有微生物的集合。居住在胃肠道中的微生物，强调了肠道微生物在胃肠道中的作用糖尿病的发生和改善。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。益生元是改变肠道的更有前途的饮食策略之一微生物群组成并改善代谢失调。低聚果糖治疗 (OFS) 是一种不可消化的纤维，可降低血糖水平，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 治疗还可以带来代谢益处，包括减肥和改善血糖宽容。尽管如此，SCFAs 如何改善葡萄糖稳态，以及这些是否益生元的有益作用所需的机制仍然未知。为了例如，小肠丙酸输注可激活肠-脑-肝轴，从而降低肝功能葡萄糖的产生，但这条途径是否存在于结肠中，大多数 SCFA 都在结肠中是否生产，未知。此外，短链脂肪酸SCFA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，丁酸盐和丙酸盐可以作为表观遗传调节因子，抑制组蛋白脱乙酰酶 (HDAC)，但目前尚不清楚 SCFAs是否影响直接调控肝脏的下游肝转录因子糖异生。根据我们的初步数据，我们得出这样的假设：短链脂肪酸 (SCFA) 可以改善通过直接和间接靶向肝葡萄糖生成（HGP）来提高葡萄糖耐量这些途径负责介导 OFS 治疗的有益效果。经过在葡萄糖耐量测试期间利用复杂的体内手术和病毒操作或胰夹，该假设将通过 3 个目标进行检验：1) 确定预吸收 SCFA 是否有效激活结肠-脑-肝轴以降低 HGP，2) 检查门静脉 SCFA 抑制的能力 HDAC 活性可降低 HGP，以及 3) 确定肠-脑-肝轴信号传导或肝 HDAC 由于 SCFA 增加，抑制作用是益生元发挥葡萄糖调节作用的原因。更好地了解益生元和短链脂肪酸如何改善葡萄糖稳态可能会导致减少糖尿病期间长期升高的 HGP 的靶向治疗。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The Gut Microbiome: Connecting Diet, Glucose Homeostasis, and Disease.

肠道微生物组：饮食、血糖稳态和疾病之间的联系。

DOI：
发表时间：
2022
期刊：
影响因子：
0
作者：
Howard, Elizabeth J;Lam, Tony K T;Duca, Frank A
通讯作者：
Duca, Frank A

Silencing gut CCK cells alters gut reaction to sugar.

沉默肠道 CCK 细胞会改变肠道对糖的反应。

DOI：
发表时间：
2022-02
期刊：
影响因子：
25
作者：
Yue, Jessica T Y;Duca, Frank A;Lam, Tony K T
通讯作者：
Lam, Tony K T

Small intestinal metabolomics analysis reveals differentially regulated metabolite profiles in obese rats and with prebiotic supplementation.

小肠代谢组学分析揭示了肥胖大鼠和益生元补充剂的差异调节代谢谱。

DOI：
发表时间：
2022-07-23
期刊：
影响因子：
0
作者：
Meyer, Rachel K;Bime, Megan A;Duca, Frank A
通讯作者：
Duca, Frank A

Bye, bye, bile: how altered bile acid composition changes small intestinal lipid sensing.

再见，胆汁：胆汁酸成分的改变如何改变小肠脂质感应。

DOI：
发表时间：
2020
期刊：
影响因子：
24.5
作者：
Duca, Frank A;Lam, Tony K T
通讯作者：
Lam, Tony K T

Differential effects of plant-based flours on metabolic homeostasis and the gut microbiota in high-fat fed rats.

植物性面粉对高脂喂养大鼠代谢稳态和肠道微生物群的不同影响。

DOI：
发表时间：
2023-10-19
期刊：
影响因子：
4.5
作者：
Martinez, Taylor M;Wachsmuth, Hallie R;Meyer, Rachel K;Weninger, Savanna N;Lane, Adelina I;Kangath, Archana;Schiro, Gabriele;Laubitz, Daniel;Stern, Jennifer H;Duca, Frank A
通讯作者：
Duca, Frank A