Effects of Palmitic Acid Hydroxy Stearic Acids (PAHSAs) on Intestinal Mucosal Biology for the Treatment of Type 2 Diabetes

棕榈酸羟基硬脂酸 (PAHSA) 对肠粘膜生物学的影响用于治疗 2 型糖尿病

基本信息

批准号：
10382051
负责人：
Jennifer Lee
金额：
$ 7.69万
依托单位：
BETH ISRAEL DEACONESS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2022-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10382051
关键词：
Adaptive Immune System Address Adipose tissue Anti-Inflammatory Agents Antidiabetic Drugs Antiinflammatory Effect Attenuated Automobile Driving Bacteroides thetaiotaomicron Biology Body Weight Cecum Cells Colitis Data Development Environment Esters Family Gastrointestinal tract structure Goals Grant Gut Mucosa Health High Fat Diet Homeostasis Human Hydroxy Acids Immune Immune response Immune system Impairment Inflammation Inflammatory Insulin Insulin Resistance Interleukin-1 beta Intestinal Mucosa Intestines K-Series Research Career Programs Lead Lipids Lipopolysaccharides Measures Mediating Mentorship Metabolic Diseases Metabolic Pathway Metabolism Microbe Mus Non-Insulin-Dependent Diabetes Mellitus Obese Mice Obesity Palmitic Acids Pathologic Peripheral Play Probiotics Production Propionates Research Rodent Role Serum Stearic Acids T cell response T-Lymphocyte Therapeutic Thinness Tissues Training Volatile Fatty Acids Weight Gain Work base blood glucose regulation career cytokine diabetic diet-induced obesity experience gastrointestinal glucose metabolism glucose tolerance gut dysbiosis gut microbes gut microbiome gut microbiota improved inflammatory disease of the intestine innovation insulin sensitivity metabolic endotoxemia metabolic phenotype metabolome metagenome metagenomic sequencing novel novel therapeutic intervention obesity development oral supplementation probiotic supplementation response targeted treatment

项目摘要

OMB No. 0925-0001 (Rev. 03/2020 Approved Through 02/28/2023) Project Summary Obesity-induced inflammation contributes to the development of insulin resistance and Type 2 Diabetes (T2D). The gut plays an important yet poorly understood role in the development of T2D. Mounting evidence implicates impaired intestinal immune responses and dysbiosis of the gut microbiota in driving the onset of insulin resistance. Recently, a novel family of lipids called Palmitic Acid Hydroxy Stearic Acids (PAHSAs) was discovered that are anti-inflammatory and anti-diabetic. Preliminary data demonstrates that PAHSAs improve glucose homeostasis in insulin-resistant mice and this is associated with reduced intestinal inflammation and favorable shifts to gut microbial species that associate with leanness. Functional analyses of the cecal metabolome and metagenome from mice treated with PAHSA lipids has identified a probiotic that strongly associates with insulin sensitivity in these same mice. Daily oral supplementation with this probiotic has beneficial effects to reduce body weight gain and improve glucose homeostasis in conventional chow and high fat diet (HFD)-fed mice. Our central hypothesis is that the gut plays an important role in mediating the beneficial effects of PAHSAs on glucose homeostasis. The goals of this proposal are to 1) identify whether PAHSA effects on improved gut barrier function and glucose metabolism are mediated by gut T-cells, and 2) defining the cecal and serum metabolome from mice supplemented with the gut microbe that associates with insulin sensitivity in PAHSA-treated mice. This grant will define the mechanisms by which PAHSAs and beneficial gut microbes improve gut mucosal homeostasis and contribute to regulating glucose metabolism. These studies may reveal novel therapeutic strategies and targets that beneficially leverage gut immune responses and the gut microbiome to treat obesity and insulin resistance in humans.

OMB No. 0925-0001（Rev. 03/2020通过02/28/2023批准）项目摘要肥胖引起的炎症有助于胰岛素抵抗的发展和2型糖尿病（T2D）。肠道在T2D的发展中起着重要但知之甚少的作用。越来越多的证据暗示肠道免疫反应受损和肠道微生物群的营养不良，在驱动胰岛素的发作中反抗。最近，一个新型的脂质家族称为棕榈酸羟基耐甲酸（PAHSA）是发现具有抗炎和抗糖尿病的人。初步数据表明PAHSA有所改善胰岛素耐药性小鼠中的葡萄糖稳态，这与肠道炎症减少有关有利的转移向与瘦身相关的肠道微生物物种。盲肠的功能分析来自PAHSA脂质治疗的小鼠的代谢组和元基因组已经确定了强烈的益生菌在这些小鼠中与胰岛素敏感性相关。每天用这种益生菌补充口服有益降低体重增加并改善常规食物和高脂饮食中的葡萄糖稳态的影响（HFD） - 食小鼠。我们的核心假设是肠道在介导有益作用中起着重要作用 Pahsas的葡萄糖稳态。该提议的目标是1）确定PAHSA是否对改善的肠道屏障功能和葡萄糖代谢是由肠道T细胞介导的，2）定义盲肠和来自补充肠道微生物的小鼠的血清代谢组，与胰岛素敏感性相关 PAHSA治疗的小鼠。该赠款将定义PAHSA和有益肠道微生物的机制改善肠道粘膜稳态，并有助于调节葡萄糖代谢。这些研究可能揭示新颖的治疗策略和目标，可以利用肠道免疫反应和肠道微生物组治疗人类的肥胖和胰岛素抵抗。