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

OMB 编号 0925-0001（修订版 03/2020 批准至 2023 年 2 月 28 日） 项目概要 肥胖引起的炎症会导致胰岛素抵抗和 2 型糖尿病的发生 （T2D）。肠道在 T2D 的发展中发挥着重要但人们知之甚少的作用。越来越多的证据 表明肠道免疫反应受损和肠道微生物群失调导致胰岛素的产生 阻力。最近，一种名为棕榈酸羟基硬脂酸（PAHSA）的新型脂质家族被开发出来。 发现具有抗炎和抗糖尿病作用。初步数据表明 PAHSA 改善 胰岛素抵抗小鼠的葡萄糖稳态，这与减少肠道炎症和 与瘦身相关的肠道微生物种类的有利转变。盲肠的功能分析 经过 PAHSA 脂质处理的小鼠的代谢组和宏基因组已鉴定出一种益生菌，它可以强烈 与这些小鼠的胰岛素敏感性相关。每日口服补充这种益生菌有益 在传统饲料和高脂肪饮食中减少体重增加和改善葡萄糖稳态的效果 (HFD) 喂养的小鼠。我们的中心假设是肠道在调节有益作用方面发挥着重要作用 PAHSA 对葡萄糖稳态的影响。该提案的目标是 1) 确定 PAHSA 是否影响 改善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 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 处理的小鼠。这笔赠款将定义 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 有益地利用肠道免疫反应和肠道微生物组的新颖治疗策略和目标 治疗人类肥胖和胰岛素抵抗。

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.