Ontology highlight
ABSTRACT:
PROVIDER: PRJNA756295 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR15566422_1.fastq.gz | Fastqsanger.gz | |||
| SRR15566422_2.fastq.gz | Fastqsanger.gz | |||
| SRR15566423_1.fastq.gz | Fastqsanger.gz | |||
| SRR15566423_2.fastq.gz | Fastqsanger.gz | |||
| SRR15566424.fastq.gz | Fastqsanger.gz |
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Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.
2022-09-23 | GSE184261 | GEO
Project description:A greater understanding of the glucose homeostasis mediated by glucagon-like peptide-1 (GLP-1) will facilitate the development of novel glucose-lowering treatments. Here we show that improved glucose metabolism in hypothyroid mice after treatment of T3, the active form of thyroid hormone (TH), is accompanied with increased GLP-1 production and insulin secretion. Treatment of a GLP-1 receptor antagonist is able to attenuate the observed T3 effect on insulin and glucose levels, suggesting that GLP-1 is critically involved in the regulation of glucose homeostasis by T3. By using a mouse model lacking hepatic TH receptor β (TRβ) and a liver-specific TRβ-selective agonist, we demonstrate that TRβ-mediated hepatic TH signalling is not only required for the regulation of GLP-1 production by T3 but also the insulinotropic and glucose-lowering effects of T3. Accordingly, administration of the liver-targeted TRβ-selective agonist is capable of increasing GLP-1 and insulin levels and alleviating hyperglycemia in diet-induced obesity. Mechanistically, through suppressing CYP8B1 expression, T3 shapes the bile acid (BA) composition and increases the levels of Farnesoid X receptor (FXR)-antagonistic BAs, thereby potentiating the GLP-1 production and insulin secretion by repressing intestinal FXR signalling. Consistently, correlations between the T3 levels and either GLP-1 or FXR-antagonistic BA levels can be observed in euthyroid human subjects. Thus, our study reveals a previously undescribed role of hepatic TH signalling in glucose homeostasis through the regulation of GLP-1 production via BA-mediated FXR antagonism, which will underpin the development of novel therapeutics.
2022-09-23 | GSE184055 | GEO
Project description:Obesity has emerged as a common disease worldwide. Risks of developing other metabolic diseases, such as Type 2 diabetes are also higher in obese population. However, current treatment options are limited. Here we discovered a new approach for mitigating obesity and metabolic disorders by targeting intestinal nuclear receptor corepressor (NCoR). In mice with diet-induced obesity, NCoR deficiency in intestinal epithelial cells (IECs) improved obesity, insulin resistance, and glucose intolerance, corrected atherogenic dyslipidemia, and reduced hepatic steatosis. These effects were mediated through regulation of energy expenditure, energy harvest, and gut hormone secretion. Mechanistically, NCoR deficiency in IECs stimulated peroxisome proliferator-activated receptor α (PPARα) signaling pathway-mediated succinate production and thermogenesis. Intestinal cholesterol excretion was induced by derepression of intestinal liver X receptor (LXR), and triglyceride and fatty acid absorption in the upper intestine was reduced by disrupted bile acid synthesis and altered bile acid composition. In the distal intestine, increased fatty acid uptake stimulated glucagon-like peptide-1 (GLP-1) secretion and improved glycemic control.
2024-08-01 | GSE237833 | GEO
Project description:Bariatric surgeries remain the most effective treatments for sustained weight loss and remission of type 2 diabetes. In addition to decreased body weight and improved glucose regulation, these procedures also dramatically increase secretion of several gut hormones including GLP-1. Despite these benefits, there are deleterious side effects to these procedures that include an increased incidence of iron-deficiency related anemias. The transcription factor HIF2a is heavily expressed in the duodenum and regulates the molecular machinery of iron absorption from the lumen. Lower iron levels after both gastric bypass and sleeve gastrectomy procedures occur despite dramatic upregulation of HIF2a signaling in the duodenum and are likely the result of increased hepcidin levels. Low iron diets also stimulate increased HIF2a signaling in the duodenum and produce effects similar to bariatric surgery that include reduced body weight/fat, improved glucose regulation and increased secretion of the GLP-1. Gut-specific deletion of VHL results in a constitutive upregulation of HIF2a signaling in the small intestine and produces a dramatic phenotype that includes reduced body weight/fat, improved glucose tolerance and increased GLP-1 secretion from the intestine. These data demonstrate an important role of HIF2a signaling in the duodenum to regulate multiple aspects of systemic metabolism and gut hormone secretion pointing towards critical cross-talk between the systems that regulate iron and other aspects of systemic physiology important to prevalent metabolic diseases.
2022-02-03 | GSE169402 | GEO
Project description:Bariatric surgeries remain the most effective treatments for sustained weight loss and remission of type 2 diabetes. In addition to decreased body weight and improved glucose regulation, these procedures also dramatically increase secretion of several gut hormones including GLP-1. Despite these benefits, there are deleterious side effects to these procedures that include an increased incidence of iron-deficiency related anemias. The transcription factor HIF2a is heavily expressed in the duodenum and regulates the molecular machinery of iron absorption from the lumen. Lower iron levels after both gastric bypass and sleeve gastrectomy procedures occur despite dramatic upregulation of HIF2a signaling in the duodenum and are likely the result of increased hepcidin levels. Low iron diets also stimulate increased HIF2a signaling in the duodenum and produce effects similar to bariatric surgery that include reduced body weight/fat, improved glucose regulation and increased secretion of the GLP-1. Gut-specific deletion of VHL results in a constitutive upregulation of HIF2a signaling in the small intestine and produces a dramatic phenotype that includes reduced body weight/fat, improved glucose tolerance and increased GLP-1 secretion from the intestine. These data demonstrate an important role of HIF2a signaling in the duodenum to regulate multiple aspects of systemic metabolism and gut hormone secretion pointing towards critical cross-talk between the systems that regulate iron and other aspects of systemic physiology important to prevalent metabolic diseases.
2022-02-03 | GSE169400 | GEO
Project description:The gut microbiome is a key factor regulating energy-metabolism, glucose tolerance and the immune system. Akkermansia muciniphila has been identified as being beneficial gut bacterium for metabolic diseases, including obesity and type 2 diabetes (T2D); however, the molecular mechanisms involved in host interactions have yet to be known. Here, we described the effects of A. muciniphila on thermogenesis and GLP-1 secretion through the specific secretory protein produced by A. muciniphila and its mode of action. A. muciniphila significantly elevated thermogenesis with induction of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) and systemic glucagon-like peptide-1 (GLP-1) secretion. Using fast protein liquid chromatography (FPLC) and liquid chromatography (LC)-mass spectrophotometry (MS)/MS analysis, we discovered that a novel 84-kDa protein, P9 is secreted by A. muciniphila and this protein improves obesity and glucose tolerance by inducing GLP-1 secretion and BAT thermogenesis. P9 induces GLP-1 secretion with direct interaction with the specific host protein, intercellular adhesion molecule-2 (ICAM-2), via IL-6 dependent pathway. This novel host-microbe interaction between P9 and ICAM-2 may become a therapeutic target for metabolic diseases.
2021-01-13 | MTBLS1824 | MetaboLights
Project description:The Glucagon-Like Peptide-1 (GLP-1) is a proglucagon-derived peptide with regulatory effects on many tissues, including the pancreas, stomach, liver, brain and heart. The rapid inactivation of intestinally secreted GLP-1 by DPP-4 enzyme raises the question of its production in proximity of its targets. Here we show some epithelial cells producing GLP-1 in the stomach of rats and humans. These cells respond specifically to intragastric load of glucose by increasing GLP-1 levels in the portal vein, in vivo in the rat. GLP-1 is known as an incretin, it decreases blood glucose levels after a meal by increasing insulin secretion in response to glucose. The increased GLP-1 secretion in obese individuals who have undergone bariatric surgery is considered as a keystone in the glycemic improvement observed in those patients. Here we show that obese rats that underwent RYGB or VSG exhibit a new gastric mucosa phenotype with expansion and hyperplasia of the mucus neck cells, and increased density of gastric GLP-1 expressing cells compared to sham animals. These findings highlight a potential role of stomach-derived GLP-1 in the outcomes of bariatric surgeries and raise the question of its role in physiology and metabolism.
2020-12-04 | PXD009867 | Pride
Project description:Deterioration of functional islet β-cell mass is the final step in progression to Type 2 diabetes. We previously reported that overexpression of Nkx6.1 in rat islets has the dual effects of enhancing glucose-stimulated insulin secretion (GSIS) and increasing β-cell replication. Here we show that Nkx6.1 strongly upregulates the prohormone VGF in rat islets and that VGF is both necessary and sufficient for Nkx6.1-mediated enhancement of GSIS. Moreover, the VGF-derived peptide TLQP-21 potentiates GSIS in rat and human islets and improves glucose tolerance in vivo. Chronic injection of TLQP-21 in pre-diabetic ZDF rats preserves islet mass and slows diabetes onset. TLQP-21 prevents islet cell apoptosis by a pathway similar to that used by GLP-1, but independent of the GLP-1, GIP, or VIP receptors. Unlike GLP-1, TLQP-21 does not inhibit gastric emptying or increase heart rate. We conclude that a TLQP-21 is a novel agent for enhancing islet β-cell survival and function.
2012-05-10 | GSE37852 | GEO
Project description:The novel Traditional Chinese Medicine Ramulus Mori (Sangzhi) alkaloid tablets (SZ-A) are approved by The China National Medical Products Administration for the treatment of type 2 diabetes mellitus (T2DM). However, the extensive pharmacological characteristics and the underlying mechanism are unknown. This study investigated the mechanisms by which SZ-A ameliorates glucose metabolism in KKAy mice, an animal model of T2DM. Diabetic KKAy mice were treated intragastrically with SZ-A once daily for 8 weeks, after which glucose levels, lipid metabolism, gut microbiome, systemic inflammatory factors, luminal concentrations of short-chain fatty acids (fecal samples), and ileal proteomic changes were evaluated. The ileum tissues were collected, and the effects of SZ-A on pathological inflammatory damage were evaluated by hematoxylin and eosin staining, immunofluorescence, and immunohistochemistry. The mRNA and protein expression levels of various inflammatory markers, including monocyte chemoattractant protein-1 and phosphorylated nuclear factor kappa B p65, were detected in the ileum tissues. SZ-A improved glucose metabolism with enhanced insulin response and elevated glucagon-like peptide 1 (GLP-1) during the glucose tolerance test in diabetic KKAy mice. Gut microbiota analysis demonstrated that SZ-A administration elevated the abundance of Bacteroidaceae and Verrucomicrobia, reduced the levels of Rikenellaceae and Desulfovibrionaceae; and increased the concentrations of fecal acetic and propionic acids compared to the diabetic model group. Additionally, SZ-A markedly improved ileal inflammatory injury and pro-inflammatory macrophage infiltration and improved intestinal mucosal barrier function in diabetic KKAy mice. SZ-A also attenuated the levels of circulating endotoxin, pro-inflammatory cytokines, and chemokines in the mice sera. Collectively, SZ-A ameliorated the overall metabolic profile including glucose and lipid metabolism in KKAy mice, which may be associated with an improvement in GLP-1 and insulin secretion, at least in part by modulating the gut microbiome and relieving the degree of ileal and systemic inflammation.
2021-09-10 | PXD024241 | Pride
Project description:Antibiotic induced microbiome depletion (AIMD) has been used frequently to study the role of the gut microbiome in pathological conditions. However, unlike germ-free mice, the effects of AIMD on host metabolism is unknown. We investigated the effects of AIMD in normal-chow fed mice to understand its effects on gut homeostasis, luminal signaling, and metabolism. We show that AIMD, which decreases luminal Firmicutes and Bacteroidetes species, decreases baseline serum glucose levels, reduces glucose surge in a tolerance test, and improves insulin sensitivity without altering adiposity. These occur in the setting of decreased luminal short-chain fatty acids (SCFAs), especially butyrate, and secondary bile acid (BA) pool, which affects whole-body BA metabolism. In mice, AIMD alters cecal gene expression and gut GLP-1 signaling. Extensive tissue remodeling and decreased availability of SCFAs shift colonocyte metabolism toward glucose utilization. Hence, AIMD alters whole-body glucose homeostasis by potentially shifting colonocyte energy utilization from SCFAs to glucose.
2018-07-07 | GSE114818 | GEO