Intestinal Reg3g as a mediator of dietary, pharmacological and surgical therapies for obesity and diabetes

肠道 Reg3g 作为肥胖和糖尿病饮食、药物和手术治疗的中介

• 批准号: 10654019
• 负责人: RANDY J SEELEY
• 金额: $ 53.72万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654019
• 关键词: Affect; Bacteria; Biology; Body Weight; Body fat; Calories; Cellular Stress; Central Nervous System; Circulation; Communication; Data; Development; Diabetes Mellitus; Diet; Disease; Functional disorder; Gastrectomy; Gastric Emptying; Gastrointestinal Diseases; Gastrointestinal Hormones; Gastrointestinal tract structure; Glucose; High Fat Diet; Hormones; Human; Inflammation; Intervention; Intestines; Inulin; Knockout Mice; Lactobacillus; Mediator; Medical; Metabolic; Metabolic Diseases; Metabolism; Metformin; Mucous body substance; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Obesity; Operative Surgical Procedures; Oral Administration; Organoids; Outcome; Oxidative Stress; Paneth Cells; Pathology; Pharmacological Treatment; Pharmacology; Prevalence; Probiotics; Production; Regenerating islet derived protein 3-Gamma; Regenerative capacity; Regulation; Reverse engineering; Role; Signal Transduction; Small Intestines; Source; Testing; Tight Junctions; Toxin; Work; absorption; antimicrobial peptide; bariatric surgery; blood glucose regulation; body system; cost; dietary; dietary supplements; effective therapy; energy balance; gastrointestinal; glucose metabolism; glucose tolerance; gut health; gut microbiome; gut microbiota; improved; in vivo Model; insulin secretion; intestinal barrier; novel; novel therapeutic intervention; obesity management; obesity treatment; pharmacologic; prevent; reduced food intake; response; segregation; soluble fiber; tool; treatment strategy

The gastrointestinal (GI) tract has become an important source for our most effective therapies to manage obesity and type 2 diabetes. This includes both surgical interventions, such as vertical sleeve gastrectomy (VSG), as well as pharmacological agents that mimic the effects of one or more GI hormones. Despite this, there remains a great deal unknown about the impact of the GI tract on systemic metabolism and the regulation of energy balance. The GI tract is uniquely situated because it must compromise between keeping out toxins and bacteria while simultaneously absorbing necessary calories and nutrients. The gut-barrier keeps host and bacteria appropriately segregated using both physical components such as tight junctions and mucus production, as well as secreted factors such as anti-microbial peptides. One such anti-microbial peptide is Reg3g (regenerating islet-derived protein 3 gamma) is abundantly secreted by paneth cells in the small intestine. We have spent the last 4 years carefully documenting how Reg3g regulates gut function, energy balance and glucose levels in response to VSG. Bariatric surgeries such as VSG greatly increase gastric emptying rates, placing an enormous burden on the intestine. This results in many intestinal adaptations, which includes increasing the prevalence and abundance of Lactobacillus as well as increasing both expression and circulating levels of Reg3g. We found that Reg3g knockout (KO) mice fail to mount many of these important adaptations, including an increase in the integrity of the gut-barrier. Importantly, these mice also fail to lose significant body fat, improve their glucose tolerance and increase their insulin secretion after VSG. Moreover, pharmacological administration of Reg3g in the periphery improved glucose tolerance, and direct administration of Reg3g in the central nervous system (CNS) reduced food intake. These results support our overarching hypothesis that Reg3g acts both within the lumen and as a circulating gut hormone to regulate energy balance and glucose levels in effective dietary, surgical and pharmacological therapies. We will test this overarching hypothesis in 3 aims: Specific Aim 1: To test the hypothesis that dietary and pharmacological treatments that improve glucose regulation and increase Lactobacillus exert key beneficial effects by increasing the expression and/or circulating levels of intestinal Reg3g. Our data show that VSG increases Lactobacillus and both intestinal expression and circulating levels of Reg3g. In addition, we found that Reg3g is required for many of the positive metabolic outcomes of VSG. Both oral administration of metformin and diets high in the soluble fiber inulin also increase the abundance of Lactobacilli in the small intestine and improve glucose regulation, such as occurs with VSG. We hypothesize that these interventions will also increase Reg3g in the intestine and in circulation and that Reg3g will be essential for metformin and inulin to improve gut function, body weight and glucose regulation. We will use these interventions in WT and Reg3g KO mice to test this hypothesis. Specific Aim 2: To test whether intestinal microbiota and its products can produce beneficial effects on GI and metabolic function by increasing intestinal Reg3g. First, we will administer a variety of probiotics to mice and test their ability to increase Reg3g intestinal expression and circulating levels. These probiotics will include various species of Lactobacillus or a pre and probiotic combination that can also produce lactate. Then, we will determine whether their effects on gut function, energy balance and glucose regulation are dependent on Reg3g using WT and Reg3g KO mice. Despite the centrality of the gut for treatments of obesity and diabetes, the relationship between the intestinal microbiome, gut health and metabolic regulation is fraught with unanswered questions. This proposal hypothesizes a novel role for Reg3g as a signal that communicates the status of intestinal bacteria and the gut barrier to regulate multiple aspects of systemic metabolism. As such, the proposed work provides a new framework for understanding how the gut affects metabolic disease and opens new therapeutic approaches that might range from dietary supplements and pharmacology to surgical procedures that can harness Reg3g biology to prevent and/or treat GI and metabolic disease.

胃肠道（GI）已经成为我们最有效的治疗肥胖和2型糖尿病的重要来源。这包括外科干预，如垂直袖状胃切除术（VSG），以及模拟一种或多种GI激素作用的药理学药物。尽管如此，关于胃肠道对全身代谢和能量平衡调节的影响仍然有很多未知数。 胃肠道是独特的，因为它必须在保持毒素和细菌之间做出妥协，同时吸收必要的热量和营养。肠道屏障使用诸如紧密连接和粘液产生的物理组分以及诸如抗微生物肽的分泌因子来保持宿主和细菌适当地隔离。一种这样的抗微生物肽是Reg 3g（再生胰岛衍生蛋白3 γ），其由小肠中的潘氏细胞大量分泌。在过去的4年里，我们仔细记录了Reg 3g如何调节肠道功能，能量平衡和葡萄糖水平以响应VSG。 减肥手术如VSG大大增加胃排空率，对肠道造成巨大负担。这导致许多肠道适应，包括增加乳酸杆菌的流行和丰度以及增加Reg 3g的表达和循环水平。我们发现，Reg 3g敲除（KO）小鼠未能安装许多这些重要的适应，包括增加肠道屏障的完整性。重要的是，这些小鼠在VSG后也未能显著减少体脂，改善其葡萄糖耐量并增加其胰岛素分泌。此外，外周给予Reg 3g可改善葡萄糖耐量，中枢神经系统（CNS）直接给予Reg 3g可减少食物摄入。这些结果支持我们的总体假设，即Reg 3g在管腔内和作为循环肠道激素发挥作用，以调节有效饮食，手术和药理学治疗中的能量平衡和葡萄糖水平。我们将在3个目标中测试这一总体假设： 具体目标1：检验改善葡萄糖调节和增加乳酸杆菌的饮食和药物治疗通过增加肠道Reg 3g的表达和/或循环水平发挥关键有益作用的假设。我们的数据表明，VSG增加乳酸杆菌和肠道表达和循环水平的Reg 3g。此外，我们发现Reg 3g是VSG的许多积极代谢结果所必需的。口服二甲双胍和富含可溶性纤维菊粉的饮食也增加了小肠中乳酸杆菌的丰度并改善葡萄糖调节，例如VSG。我们假设这些干预措施也会增加肠道和循环中的Reg 3g，并且Reg 3g对于二甲双胍和菊粉改善肠道功能，体重和葡萄糖调节至关重要。我们将在WT和Reg 3g KO小鼠中使用这些干预措施来检验这一假设。 具体目标二：测试肠道微生物群及其产物是否可以通过增加肠道Reg 3g对GI和代谢功能产生有益影响。首先，我们将向小鼠施用各种益生菌，并测试它们增加Reg 3g肠道表达和循环水平的能力。这些益生菌将包括各种乳酸杆菌或前益生菌组合，也可以产生乳酸。然后，我们将使用WT和Reg 3g KO小鼠确定它们对肠道功能、能量平衡和葡萄糖调节的影响是否依赖于Reg 3g。 尽管肠道在肥胖和糖尿病治疗中处于中心地位，但肠道微生物组，肠道健康和代谢调节之间的关系充满了未回答的问题。该提案假设Reg 3g作为一种信号的新作用，该信号传达肠道细菌和肠道屏障的状态，以调节全身代谢的多个方面。因此，拟议的工作为理解肠道如何影响代谢疾病提供了一个新的框架，并开辟了新的治疗方法，范围从膳食补充剂和药理学到外科手术，可以利用Reg 3g生物学来预防和/或治疗GI和代谢疾病。