Acarbose improves obesity-induced insulin resistance and immune homeostasis by directly regulating gut microbiota and macrophages inflammation
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ABSTRACT:
PROVIDER: PRJNA972753 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24572181_1.fastq.gz | Fastqsanger.gz | |||
| SRR24572181_2.fastq.gz | Fastqsanger.gz | |||
| SRR24572182_1.fastq.gz | Fastqsanger.gz | |||
| SRR24572182_2.fastq.gz | Fastqsanger.gz | |||
| SRR24572183_1.fastq.gz | Fastqsanger.gz |
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Project description:Acarbose was reported to alleviate obesity-induced insulin resistance IR and regulate the gut microbiota community; however, the critical microbial signaling metabolites and the host targets associated with the metabolic benefits of acarbose remains unknown. In this study, we reported that acarbose treatment was able to significantly improve high fat diet (HFD) induced IR and inflammation states in adipose tissue and intestine by influencing the survival and pro-inflammatory function of M1 macrophages. Furthermore, we revealed that acarbose exert anti-inflammatory effects partly in a gut-microbiota dependent manner by microbiota clearance experiments. 16S rRNA sequencing and metabolomic researches identified that acarbose could enhance the proliferation of propionic acid (PA)-producing Parasutterella excrementihominis (PARA). As the vital metabolic mediator, PA regulated the pro-inflammatory and anti-inflammatory balance of M1/M2 macrophages by GPR4/NLRP3 signaling pathway. In addition, in vivo studies of NBD fluorescence labeled acarbose verified that acarbose directly inhibited the macrophage inflammatory response in adipose tissue via being captured by intestinal macrophage due to the aggravated intestinal permeability in HFD mice. We also validated this result in bone-marrow derived macrophage (BMDM) and human macrophages in vitro. Mechanistically, acarbose may suppressed mTOR signaling pathway and the following autophagy/mitochondrial function of M1 macrophage by activating GPR120, thereby reducing its survival and the secretion of pro-inflammatory cytokines. In conclusion, these findings presented that acarbose improved obesity-induced IR by maintaining beneficial microbiota and direct inhibited action on M1 macrophages.
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Project description:Insulin resistance is the hallmark of obese and type 2 diabetes patients. Defective insulin sensitivity in the liver results in increased glucsoe production, which is the major cause of hyperglycemia in diabetic patients. Increased lipopolysaccharide (LPS) leakage from the gut of diet-induced obesity causes insulin resisitance; moreover, activation of deacetylase Sirtuin1 restore insulin sensitivity in obesity. However, the mechanism resulting in insulin resistance by LPS remains poorly understood. Here, we show that Ep300 (P300) harboring an intrinsic acetyltransferase activity was rapidly induced in the liver of animals fed a high-fat diet, and the induction of Ep300 is through LPS-stimulated activation of ER stress. Induced Ep300 impairs insulin signaling by acetylating mediators in insulin signaling. Inhibition of P300 acetyltransferase activity improves insulin signaling. Thus, Ep300 acetyltransferase activity is a therapeutic target.
2017-05-08 | GSE86108 | GEO
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Project description:Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here, we report that IL-37, a newly-described antiinflammatory member of the IL-1 family, affects obesity-induced inflammation and insulin resistance. IL-37 transgenic mice (IL-37tg) did not develop an obese phenotype in response to a high-fat diet (HFD). Unlike WT mice, IL-37tg mice exhibited reduced numbers of adipose tissue macrophages and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. A short-term HFD intervention revealed that the IL-37-mediated improvement in glucose tolerance is independent of bodyweight. IL-37tg mice manifested a beneficial metabolic profile with higher circulating levels of the anti-inflammatory adipokine adiponectin. In vitro treatment of differentiating adipocytes with recombinant IL-37 reduced adipogenesis. The beneficial effects of recombinant IL-37 involved activation of AMPK signaling. In humans, steady-state IL-37 adipose tissue mRNA levels were positively correlated with insulin sensitivity, lower adipose tissue levels of leptin and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes. Gene arrays were performed on epidydimal white adipose tissue samples from wild type and human IL37-overexpressing transgenic mice fed a high fat diet for 16 weeks.
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Project description:The insulin inhibitory receptor (inceptor) was recently identified as a key terminator of insulin and insulin-like growth factor 1 receptor (INSR/IGF1R) signaling in pancreatic ?-cells12. Yet, the relevance of ?-cell inceptor for glucose regulation through the INS1R/IGF1R axis has only been demonstrated for normoglycemic and insulin sensitive lean mice, questioning whether inceptor regulation of INS1R/IGF1R action also plays a role in glucose metabolism under conditions of diet-induced obesity and insulin resistance. Here we demonstrate that whole-body germline loss of inceptor improves glucose metabolism in diet-induced obese mice with only minimal effects on weight and body composition. To assess the effect in different tissues we performed proteomics in the global, neuronal and beta cell specific mouse knock-outs.
2024-01-17 | PXD046256 | Pride
Project description:Cytokines of the IL-1 family are important modulators of obesity-induced inflammation and the development of systemic insulin resistance. Here, we report that IL-37, a newly-described antiinflammatory member of the IL-1 family, affects obesity-induced inflammation and insulin resistance. IL-37 transgenic mice (IL-37tg) did not develop an obese phenotype in response to a high-fat diet (HFD). Unlike WT mice, IL-37tg mice exhibited reduced numbers of adipose tissue macrophages and preserved glucose tolerance and insulin sensitivity after 16 weeks of HFD. A short-term HFD intervention revealed that the IL-37-mediated improvement in glucose tolerance is independent of bodyweight. IL-37tg mice manifested a beneficial metabolic profile with higher circulating levels of the anti-inflammatory adipokine adiponectin. In vitro treatment of differentiating adipocytes with recombinant IL-37 reduced adipogenesis. The beneficial effects of recombinant IL-37 involved activation of AMPK signaling. In humans, steady-state IL-37 adipose tissue mRNA levels were positively correlated with insulin sensitivity, lower adipose tissue levels of leptin and a lower inflammatory status of the adipose tissue. These findings reveal IL-37 as an important anti-inflammatory modulator during obesity-induced inflammation and insulin resistance in both mice and humans and suggest that IL-37 is a potential target for the treatment of obesity-induced insulin resistance and type 2 diabetes.
2015-05-18 | GSE58952 | GEO
Project description:Our data mark GIP as a beneficial immunoregulator during obesity and suggest a novel untapped therapeutic potential for specific targeted GIP analogs. Emerging studies suggest that glucose-dependent insulin tropic polypeptide (GIP) affect obesity-associated inflammation. Yet, whether GIP can directly regulate immune cell activity and the respective metabolic consequences remained unknown. Here, we targeted GIP-receptor-deficiency to immune cells using bone marrow (BM) chimerism approach and the reconstituted chimeric mice were subjected to a high fat diet (HFD) regimen. Mice reconstituted with Gipr-/- BM gained significantly more weight, despite similar food consumption. This was accompanied by increased epididymal adipose tissue (epiWAT) mass, adipocyte hypertrophy, enhanced hepatic steatosis, insulin resistance and significant myelopoiesis in the circulation, epiWAT and inguinal adipose tissue (ingWAT). In accordance these mice also exhibited reduced energy expenditure and ingWAT beiging. Mechanistically, impaired GIP-governed regulation of S100A8/9 in myeloid cells was responsible for the perturbed energy homeostasis, increased insulin resistance and intensified inflammatory response under nutrient overload. Collectively, our results outline a beneficial immunoregulatory role for GIP in immune cells during obesity.
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Project description:Background and Aims: Insulin resistance is a key factor in the pathogenesis of NAFLD. We evaluated the importance of subcutaneous abdominal adipose tissue (SAAT) inflammation and both plasma and SAAT-derived exosomes in regulating insulin sensitivity in people with obesity and NAFLD. Methods: Adipose tissue inflammation (macrophage and T cell content and gene expression of proinflammatory cytokines), liver and whole-body insulin sensitivity (assessed by a hyperinsulinemic-euglycemic clamp and glucose tracer infusion), and 24-hour serial plasma cytokine concentrations were evaluated in three groups stratified by adiposity, insulin sensitivity and intrahepatic triglyceride (IHTG) content: 1) metabolically-healthy lean (LEAN; n=14); 2) metabolically-healthy obese with normal IHTG content (OB-NL; n=28); and 3) metabolically-unhealthy obese with NAFLD (OB-NAFLD; n=28). The effect of plasma and SAAT-derived exosomes on insulin action (insulin-stimulated Akt phosphorylation) in human skeletal muscle myotubes was assessed in a subset of participants. Results: Proinflammatory macrophages, proinflammatory CD4 and CD8 T cell populations, and gene expression of several cytokines in SAAT were greater in the OB-NAFLD than the OB-NL and LEAN groups. However, with the exception of PAI-1, which was greater in the OB-NAFLD than the LEAN and OB-NL groups, 24-hour plasma cytokine concentration areas-under-the-curve (AUC) were not different between groups. The percentage of proinflammatory macrophages and plasma PAI-1 concentration AUC were inversely correlated with both hepatic and whole-body insulin sensitivity. Compared with exosomes from OB-NL participants, plasma and SAAT-derived exosomes obtained from the OB-NAFLD group impaired insulin action in myotubes. Conclusion: These results suggest SAAT-derived exosomes and PAI-1 are involved in the pathogenesis of systemic insulin resistance in people with obesity and NAFLD. ClinicalTrials.gov number: NCT02706262.
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Project description:Bezafibrate (BEZ), a pan activator of peroxisome proliferator-activated receptors (PPARs), is generally used to treat hyperlipidemia. Clinical trials on patients suffering from type 2 diabetes indicated that BEZ also has beneficial effects on glucose metabolism, but the underlying mechanisms remain elusive. Much less is known about the function of BEZ in type 1 diabetes. Here, we show that BEZ treatment markedly improves hyperglycemia, glucose and insulin tolerance in streptozotocin (STZ)-treated mice, an insulin-deficient mouse model of type 1 diabetes presenting with very high blood glucose levels. Furthermore, BEZ-treated mice also exhibited improved metabolic flexibility as well as an enhanced mitochondrial mass and function in the liver. Our data demonstrate a beneficial effect of BEZ treatment on STZ mice reducing diabetes and suggest that BEZ ameliorates impaired glucose metabolism possibly via augmented hepatic mitochondrial performance, improved insulin sensitivity and metabolic flexibility. We performed gene expression microarray analysis on liver tissue derived from streptozotocin-treated mice treated with bezafibrate in addition.
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Project description:Natural killer T (NKT) cells are important therapeutic targets in various disease models and under clinical trials for cancer patients. However, their function in obesity and type 2 diabetes remains unclear. Our data show that adipose tissues of both mice and humans contain a population of type-1 NKT cells, whose abundance decreases with increased adiposity and insulin resistance. Although loss-of-function of NKT cells had no effect on glucose tolerance in animals with prolonged high-fat diet (HFD) feeding, activation of NKT cells by lipid agonist α-galactosylceramide (αGalCer) enhances alternative macrophage polarization in adipose tissue and improves glucose homeostasis in animals at different stages of obesity. Furthermore, the effect of NKT cells is largely mediated by the IL-4/STAT6 signaling axis in obese adipose tissue. Thus, our data identifies a novel therapeutic target for the treatment of obesity-associated inflammation and type-2 diabetes. Wild type and CD1d1 antigen (CD1d) knockout mice were fed a high fat diet for 4 days. On day 0 and 2 mice were injected intraperitoneally with α-galactosylceramide (αGalCer) or vehicle. On day 4 mice were killed and gene expression was profiled in epididymal adipose tissue.
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