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）道已成为我们管理肥胖症和2型糖尿病的最有效疗法的重要来源。这包括手术干预措施，例如垂直套筒胃切除术（VSG），以及模仿一种或多种GI激素影响的药理学剂。尽管如此，关于胃肠道对系统性代谢和能量平衡调节的影响仍然存在很多未知。 胃肠道的位置是独特的，因为它必须在保持毒素和细菌的同时吸收必要的卡路里和养分之间损害。肠道垒可以使用诸如紧密连接和粘液产生的物理成分以及分泌的因素（例如抗微生物肽）进行适当隔离的宿主和细菌。一种这样的抗微生物肽是reg3g（再生胰岛衍生的蛋白3伽马），被小肠中的泛细胞大量分泌。在过去的四年中，我们已经仔细记录了Reg3G如何调节肠道功能，能量平衡和葡萄糖水平，以响应VSG。 诸如VSG之类的减肥手术大大增加了胃排空率，给肠子带来了巨大的负担。这导致了许多肠道适应，包括增加乳酸杆菌的患病率和丰度，以及增加Reg3g的表达和循环水平。我们发现Reg3G敲除（KO）小鼠无法安装许多重要的适应性，包括肠道控架器的完整性增加。重要的是，这些小鼠还无法失去大量的体内脂肪，提高其葡萄糖耐受性并增加VSG后胰岛素分泌。此外，外围药理药理学给药可提高葡萄糖耐受性，并在中枢神经系统（CNS）中直接给药减少了食物摄入量。这些结果支持我们的总体假设，即Reg3G在管腔内起作用，也是循环肠系膜在有效的饮食，外科和药理疗法中调节能量平衡和葡萄糖水平的循环肠激素。我们将在3个目标中检验这一总体假设： 具体目的1：检验以下假设：饮食和药理学治疗可以改善葡萄糖调节并增加乳杆菌通过增加肠道reg3g的表达和/或循环水平，从而发挥关键的有益作用。我们的数据表明，VSG增加了乳杆菌，肠道表达和循环水平的Reg3g水平。此外，我们发现REG3G是VSG的许多阳性代谢结果所必需的。口服二甲双胍和饮食高可溶性纤维素的饮食均增加了小肠中乳糖核的丰度并改善了葡萄糖调节，例如VSG发生。我们假设这些干预措施还将增加肠和循环中的REG3G，而REG3G对于二甲双胍和依氨蛋白可以改善肠道功能，体重和葡萄糖调节至关重要。我们将在WT和REG3G KO小鼠中使用这些干预措施来检验该假设。 特定目的2：测试肠道菌群及其产品是否可以通过增加肠道重3G对GI和代谢功能产生有益的影响。首先，我们将对小鼠进行各种益生菌，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杆菌或也可以产生乳酸的前和益生菌组合。然后，我们将确定它们对使用WT和REG3G KO小鼠的肠道功能，能量平衡和葡萄糖调节的影响是否取决于REG3G。 尽管肠道对肥胖和糖尿病的疗法的中心地位，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解决的问题。该提议假设Reg3G的新作用是传达肠道细菌状态和肠道障碍的信号，以调节系统性代谢的多个方面。因此，拟议的工作为了解肠道如何影响代谢疾病的新框架提供了一个新的框架，并打开了新的治疗方法，这些方法可能从饮食补充剂和药理学到可以利用重新生物学的外科手术，以预防和/或治疗GI和代谢疾病。