Gut microbiota and obesity: studies in gnotobiotic mice

肠道微生物群和肥胖：对无菌小鼠的研究

基本信息

批准号：
7422345
负责人：
JEFFREY I GORDON
金额：
$ 33.41万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-08-01 至 2010-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7422345
关键词：
Adipocytes Adipose tissue Adult Affect Age Alleles Animals Antibiotics Bacteria Bacterial Typing Bacteroides Bacteroides thetaiotaomicron Binding Proteins Biological Assay Biological Markers Biology Birth Body Weight Body Weight decreased Body fat Carbohydrates Cell Nucleus Cells Cessation of life Cognitive Collection Consumption DEXA Deposition Development Diet Dietary Carbohydrates Dietary Polysaccharide Digestion Distal Dual-Energy X-Ray Absorptiometry Ecology Energy Metabolism Environmental Risk Factor Enzymes Epidemic Epithelial Equilibrium Evolution Fasting Fat-Restricted Diet Fatty Acids Fatty acid glycerol esters Fatty-acid synthase Foundations Gender Gene Targeting Genes Genetic Genetic screening method Genetically Engineered Mouse Genome Genomics Germ Germ-Free Glucose Gnotobiotic Harvest Hepatic Hepatocyte Home environment Human Hyperplasia Hypertrophy Inbred Strain Indigenous Indirect Calorimetry Insulin Insulin Resistance Intestines Knock-out Knockout Mice Lactobacillus Lead Learning Leptin Leucine Zippers Life Liver Locales Measures Mediating Mediator of activation protein Metabolic Metabolism Microbe Molecular Monosaccharides Mus Muscle NMRI Mouse Nuclear Import Numbers Nutrient Obesity Organ Pathway interactions Pentosephosphate Pathway Peripheral Phenocopy Phenotype Physiological Plants Polysaccharides Predisposition Process Production Protein Phosphatase 2A Regulatory Subunit PR53 Protein Serine/Threonine Phosphatase Proteins Rate Regulation Response Elements Role SRE-1 binding protein Serum Skeletal Muscle Standards of Weights and Measures Sterols Structure Symbiosis Techniques Testing Therapeutic Thinking Thinness Time Transgenes Tricarboxylic Acids Triglycerides Week Weight Wild Type Mouse acrosome stabilizing factor adiponectin attenuation base carbohydrate binding protein carbohydrate receptor cell type concept day energy balance feeding functional genomics genome sequencing in vivo intestinal epithelium knockout animal lipid biosynthesis lipoprotein lipase lipoprotein lipase inhibitor member microbial microbial community microbial host microbiome microorganism novel therapeutics research study response sugar transcription factor xylulose-5-phosphate

项目摘要

DESCRIPTION (provided by applicant): Developing non-cognitive approaches for treating obesity is imperative. We have been using gnotobiotic mice to examine the significance of human-bacterial symbioses in the gut, and discovered that the intestinal microbiota has a remarkable effect on fat storage. Colonization ('conventionalization') of adult germ-free (GF) C57B1/6 (B6) mice with a cecal microbiota harvested from conventionally-raised mice produces a 60% increases in total body fat content and white adipose tissue (WAT) weight. This rapid increase occurs despite decreased chow consumption and increased metabolic rate, is sustained, and accompanied by increased leptin levels, insulin resistance, and increased hepatic lipogenesis. The lipogenic response is associated with increased nuclear import of carbohydrate response element binding protein (ChREBP), modest increases in insulin-responsive SREBP-1, and trans-activation of ChREBP/SREBPl lipogenic gene targets. WAT hypertrophy is associated with increased LPL activity and intestine-specific transcriptional suppression of Fiaf (encodes a secreted LPL inhibitor). Moreover, GF Fiaf knockout mice have higher WAT LPL activity and the same body fat content as 'conventionalized' (Fiaf-suppressed) wild-type (wt) littermates: their fat stores are not increased further with conventionalization. These results suggest the following testable hypothesis: (a) microbial processing of otherwise indigestible dietary polysaccharides (PS) provides monosaccharides that lead to ChREBP, and possibly, SREBP-1- stimulation of hepatic lipogenesis: (b) microbial suppression of intestinal Fiaf, combined with the lipogenic response, promotes LPL-mediated increases in adipocyte fat storage; (c) increasing Fiaf expression and/or activity should promote leanness. Aim 1- Use wt B6 mice to determine the role of dietary carbohydrates and microbial ecology on microbiota-induced fat storage. GF and conventionalized mice will be fed isocaloric high PS/low fat, .high fat/low PS, or high sugar/low fat diets, and the effects on body fat content, VO2, feptin/glucose/insulin, WAT LPL, and intestine/liver/muscle energy metabolism assayed. Microbial requirements will be assessed by colonization with all or some components of a simplified 8-member microbiota (Altered Schaedler Flora). Aim 2- Determine the contribution of the microbiota-associated hepatic lipogenic response by conventionalizing GF mice with a ChREBP knockout, a SREBP-1 c knockout, combined ChREBP and SREBP-1 c deficiencies, or a hepatocyte-specific Fasl knockout. Aim 3- Introduce a transgene constitutively expressed in the small intestinal epithelium into Fiaf-/- mice. We predict that these mice will phenocopy leaner GF wt mice, whether or not they have been colonized [proof-of-concept genetic test of whether therapeutic manipulations that increase Fiaf expression (or activity) will promote leanness].

描述（由申请人提供）：必须开发用于治疗肥胖症的非认知方法。我们一直在使用gnotobirotic小鼠来检查肠道中人物 - 细菌共生的重要性，并发现肠道菌群对脂肪储存具有显着影响。从传统饲养小鼠收获的盲肠微生物群的成年无菌（GF）C57B1/6（B6）小鼠的定殖（“常规”）可产生60％的总体脂肪含量和白色脂肪组织（WAT）体重。尽管食用CHOW消耗降低，代谢率提高，持续，并且伴随着瘦素水平升高，胰岛素抵抗和肝脂肪生成增加，但这种快速增加还是发生了。脂肪生成反应与碳水化合物反应元件结合蛋白（CHREBP）的核进口增加有关，胰岛素反应性SREBP-1的适度增加以及CHREBP/SREBPL脂基因基因靶标的反式激活。 WAT肥大与FIAF的LPL活性增加和肠道特异性转录抑制有关（编码分泌的LPL抑制剂）。此外，GF FIAF敲除小鼠具有较高的WAT LPL活性，并且与“常规”（FIAF抑制）野生型（WT）同窝同elmates相同的体内脂肪含量：随着常规化，其脂肪存储不会进一步增加。 These results suggest the following testable hypothesis: (a) microbial processing of otherwise indigestible dietary polysaccharides (PS) provides monosaccharides that lead to ChREBP, and possibly, SREBP-1- stimulation of hepatic lipogenesis: (b) microbial suppression of intestinal Fiaf, combined with the lipogenic response, promotes LPL-mediated increases in adipocyte fat storage; （c）增加FIAF表达和/或活性应促进瘦身。目标1-使用WT B6小鼠确定饮食碳水化合物和微生物生态学对微生物群诱导的脂肪储存的作用。 GF和常规小鼠将被喂食等高PS/低脂肪，。高脂肪/低脂肪/低糖/低脂肪饮食，以及对体内脂肪含量，VO2，富肽蛋白/葡萄糖/胰岛素，WAT LPL，肠/肝/肝脏/肌肉能量代谢的影响。微生物的需求将通过与简化的8-Mybobiota（改变的Schaedler Flora）的所有或某些成分进行定殖评估。 AIM 2-通过用Chrebp敲除，SREBP-1 C敲除，CHREBP和SREBP-1 C DEFICIES或HEPATOCYTE特异性FASL淘汰赛，通过Chrebp敲除，SREBP-1 C敲除，SREBP-1 C敲除，SREBP-1 C敲除，SREBP-1 C敲除，CHREBP和SREBP-1 C敲除，确定与微生物群相关的肝脂肪性反应的贡献。 AIM 3-将在小肠上皮中组成型的转基因引入FIAF - / - 小鼠中。我们预测，这些小鼠将表现瘦的GF WT小鼠，无论它们是否已定植[概念证明基因检验，即是否会增加FIAF表达（或活性）的治疗性操纵是否会促进瘦弱的性能]。