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02/28/2023） 项目摘要 肥胖引起的炎症有助于胰岛素抵抗和2型糖尿病的发展 （T2D）。肠道在T2 D的发展中起着重要但知之甚少的作用。越来越多的证据 表明肠道免疫反应受损和肠道微生物群生态失调在驱动胰岛素作用方面发挥作用 阻力最近，一种称为棕榈酸羟基硬脂酸（PAHSAs）的新型脂质家族被发现。 有抗炎和抗糖尿病的作用。初步数据表明，PAHSAs 胰岛素抵抗小鼠的葡萄糖稳态，这与肠道炎症减少有关， 有利的转变，肠道微生物物种，与精益。盲肠的功能分析 来自用PAHSA脂质处理的小鼠的代谢组和宏基因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。每日口服补充这种益生菌， 在常规食物和高脂肪饮食中减少体重增加和改善葡萄糖稳态的作用 （HFD）喂养的小鼠。我们的中心假设是，肠道在介导有益效果方面起着重要作用 对葡萄糖稳态的影响。本提案的目标是：1）确定PAHSA是否影响 改善的肠道屏障功能和葡萄糖代谢由肠道T细胞介导，和2）限定盲肠， 来自补充有肠道微生物的小鼠的血清代谢组，该肠道微生物与胰岛素敏感性相关， PAHSA处理的小鼠。该拨款将定义PAHSAs和有益肠道微生物的机制 改善肠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应答和肠道微生物组的新型治疗策略和靶标 来治疗肥胖和胰岛素抵抗。

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.