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

管理及预算局编号0925-0001(截至2023年2月28日获批准的第03/2020版) 项目摘要 肥胖引起的炎症导致胰岛素抵抗和2型糖尿病的发生 (T2D)。肠道在T2D的发展中扮演着一个重要但知之甚少的角色。越来越多的证据 肠道免疫反应受损和肠道微生物区系失调导致胰岛素的产生 抵抗。最近，一种新的脂类被称为棕榈酸羟基硬脂酸(PAHSA)。 发现有抗炎和抗糖尿病的作用。初步数据显示，PAHSA改善了 胰岛素抵抗小鼠的葡萄糖稳态，这与减少肠道炎症和 有利的转变是肠道中与瘦身有关的微生物种类。盲肠的功能分析 PAHSA脂质处理的小鼠的代谢组和代谢组已经鉴定出一种益生菌 与这些小鼠的胰岛素敏感性有关。每天服用这种益生菌有益于 常规饮食和高脂饮食对降低体重增加和改善血糖稳态的作用 (HFD)喂养的小鼠。我们的中心假设是肠道在调节有益效果方面起着重要作用。 多环芳烃对血糖稳态的影响。这项提案的目标是1)确定PAHSA对 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 添加与胰岛素敏感性相关的肠道微生物的小鼠血清代谢物 PAHSA处理的小鼠。这笔赠款将定义PAHSA和有益的肠道微生物 改善肠道粘膜动态平衡，有助于调节葡萄糖代谢。这些研究可能会揭示 有益于利用肠道免疫反应和肠道微生物群的新治疗策略和靶点 来治疗人类的肥胖和胰岛素抵抗。

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.