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) 已成为我们治疗肥胖和 2 型糖尿病的最有效疗法的重要来源。这包括手术干预，例如垂直袖状胃切除术（VSG），以及模仿一种或多种胃肠道激素作用的药物。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存在很多未知。 胃肠道的位置独特，因为它必须在排除毒素和细菌的同时吸收必要的热量和营养之间做出妥协。肠道屏障利用紧密连接和粘液产生等物理成分以及抗菌肽等分泌因子，使宿主和细菌适当分离。 Reg3g（胰岛再生蛋白 3γ）就是这样一种抗微生物肽，由小肠中的潘氏细胞大量分泌。在过去 4 年里，我们仔细记录了 Reg3g 如何响应 VSG 调节肠道功能、能量平衡和葡萄糖水平。 VSG 等减肥手术极大地增加了胃排空率，给肠道带来了巨大的负担。这导致了许多肠道适应，包括增加乳酸菌的流行率和丰度，以及增加 Reg3g 的表达和循环水平。我们发现 Reg3g 敲除 (KO) 小鼠无法实现许多重要的适应，包括肠道屏障完整性的增强。重要的是，这些小鼠在 VSG 后也未能显着减少体脂、改善葡萄糖耐量并增加胰岛素分泌。此外，外周Reg3g的药理学给药改善了葡萄糖耐量，而中枢神经系统（CNS）中Reg3g的直接给药减少了食物摄入。这些结果支持了我们的总体假设，即 Reg3g 在管腔内发挥作用，并作为一种循环肠道激素，在有效的饮食、手术和药物治疗中调节能量平衡和葡萄糖水平。我们将通过三个目标来检验这一总体假设： 具体目标 1：检验以下假设：改善血糖调节和增加乳酸菌的饮食和药物治疗通过增加肠道 Reg3g 的表达和/或循环水平发挥关键有益作用。我们的数据表明，VSG 会增加乳酸菌以及 Reg3g 的肠道表达和循环水平。此外，我们发现 Reg3g 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会增加小肠中乳酸杆菌的丰度并改善葡萄糖调节，例如 VSG 所发生的情况。我们假设这些干预措施还将增加肠道和循环中的 Reg3g，并且 Reg3g 对于二甲双胍和菊粉改善肠道功能、体重和血糖调节至关重要。我们将在 WT 和 Reg3g KO 小鼠中使用这些干预措施来检验这一假设。 具体目标2：测试肠道菌群及其产物是否可以通过增加肠道Reg3g对胃肠道和代谢功能产生有益影响。首先，我们将给小鼠施用各种益生菌，并测试它们增加 Reg3g 肠道表达和循环水平的能力。这些益生菌将包括各种乳酸菌或也可以产生乳酸的益生菌和益生菌组合。然后，我们将使用 WT 和 Reg3g 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 Reg3g。 尽管肠道在肥胖和糖尿病的治疗中发挥着核心作用，但肠道微生物群、肠道健康和代谢调节之间的关系仍然充满了悬而未决的问题。该提议假设 Reg3g 作为传达肠道细菌和肠道屏障状态的信号来调节全身代谢的多个方面的新作用。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，范围可能从膳食补充剂和药理学到可以利用 Reg3g 生物学来预防和/或治疗胃肠道和代谢疾病的外科手术。