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Imeglimin Improves Systemic Metabolism by Targeting Brown Adipose Tissue and Gut Microbiota in Obese Model Mice

ABSTRACT: Imeglimin Improves Systemic Metabolism by Targeting Brown Adipose Tissue and Gut Microbiota in Obese Model Mice

PROVIDER: PRJNA1075028 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27927000_1.fastq.gz	Fastqsanger.gz
	SRR27927000_2.fastq.gz	Fastqsanger.gz
	SRR27927001_1.fastq.gz	Fastqsanger.gz
	SRR27927001_2.fastq.gz	Fastqsanger.gz
	SRR27927002_1.fastq.gz	Fastqsanger.gz

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Imeglimin Improves Systemic Metabolism by Targeting Brown Adipose Tissue and Gut Microbiota in Obese Model Mice

Project description:Imeglimin is a recently developed anti-diabetic drug that could concurrently promote insulin secretion and insulin sensitivity, while its mechanisms of action are not fully understood. Here we show that imeglimin administration could protect mice from high fat diet-induced weight gain with enhanced energy expenditure and attenuated whitening of brown adipose tissue. Imeglimin administration led to significant alteration of gut microbiota, which included an increase of Akkermansia genus, with attenuation of obesity-associated gut pathologies. Ablation of microbiota by antibiotic treatment partially abrogated the insulin sensitizing effects of imeglimin, while not affecting its actions on body weight gain or brown adipose tissue. Collectively, our results characterize imeglimin as a potential agent promoting energy expenditure and gut integrity, providing new insights into its mechanisms of action.

2024-02-16 | GSE255432 | GEO

Imeglimin, unlike metformin, does not perturb differentiation of human induced pluripotent stem cells towards pancreatic β-like cells and rather enhances gain in β cell identity gene sets

Project description:Aims/Introduction: Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic β cell development via impaired mitochondrial function. A new anti-diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on β cell differentiation using human induced pluripotent stem cell (iPSC)-derived pancreatic islet-like spheroid (SC-islet) models. Materials and Methods: Human iPSCs are differentiated into SC-islets by three-dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC-islets were analyzed by flow cytometry, immunostaining, quantitative PCR, and insulin secretion assay. RNA sequencing and oxygen consumption rate were obtained for further characterization of SC-islets. SC-islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP. Results: Metformin perturbed SC-islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of β cell lineage markers. Maintenance of mitochondrial function and optimization of TGF-β and Wnt signaling were considered potential mechanisms for augmented β cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated β cell differentiation impaired by cytokines and metformin. Conclusions: Imeglimin does not perturb differentiation of SC-islet cells and rather enhances gain in β cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro β cell differentiation protocols.

2025-01-20 | GSE242776 | GEO

Lrpprc deficiency in brown adipocytes diminishes cold-induced thermogenesis but improves systemic metabolism

Project description:Insufficient mitochondrial quantity in brown adipose tissue (BAT) causes defective thermogenesis and positive energy balance, which is coupled with the development of obesity. Whether disturbance of mitochondrial quality affects BAT function remains unknown. Here, we describe that the brown adipocyte-specific Leucine-rich PPR motif-containing protein knockout mice (LrpprcBKO) exhibited mitochondrial electron transport chain (ETC) proteome imbalance and a complete loss of the -adrenergic-stimulated thermogenesis at room temperature (RT), due to specific reduction of mtDNA-encoded genes. However, the LrpprcBKO mice were lean at normal chow and were protected against high-fat-diet-induced metabolic abnormalities, such as obesity, insulin resistance, adipose inflammation, hepatic steatosis, and hypertriglyceridemia. The beige adipocytes in inguinal white adipose tissue were expanded in LrpprcBKO mice at RT, but not at thermoneutrality. However, BAT thermogenic defects and metabolic benefits were present in LrpprcBKO mice regardless of ambient temperatures. Collectively, our results reveal that a thermogenesis-incapable BAT with mitochondrial ETC proteome imbalance can improve systemic metabolism, suggesting BAT’s contributions to thermoregulation and systemic metabolism can be uncoupled.

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Effects of imeglimin and metformin on islets of db/db mice

Project description:To investigate the effects of imeglimin and metformin on islet cells in db/db mice, we isolated pancreatic islets from db/db mice treated with/without imeglimin and metformin or db/+ mice.

2023-06-19 | GSE228726 | GEO

Effect of imeglimin on mitochondrial function, AMPK activity and gene expression in hepatocytes

Project description:To further understand the pharmacological properties of imeglimin, we here investigated the effects of imeglimin in hepatocytes and compared those with metformin. We investigated the genes expression in the cultured human hepatoma HepG2 cells by RNA-seq. HepG2 cells were stimulated with 0.25 mM, 3 mM metformin or imeglimin, or 1 mM AICAR, or vehicle alone for 12 h.

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Project description:Obesity and its co-morbidities including type 2 diabetes are increasing at epidemic rates in the U.S. and worldwide. Brown adipose tissue (BAT) is a potential therapeutic to combat obesity and type 2 diabetes. Increasing BAT mass by transplantation improves metabolic health in rodents, but its clinical translation remains a challenge. Here, we investigated if transplantation of 2-4 million differentiated brown pre-adipocytes from mouse BAT stromal fraction (SVF) or human pluripotent stem cells (hPSCs) could improve metabolic health. Transplantation of differentiated brown pre-adipocytes, termed ‘committed pre-adipocytes’ from BAT SVF from mice or derived from hPSCs improves glucose homeostasis and insulin sensitivity in recipient mice under conditions of diet-induced obesity, and this improvement is mediated through the collaborative actions of the liver transcriptome, tissue AKT signaling and FGF21. These data demonstrate that transplantation of a small number of brown adipocytes has significant long-term translational and therapeutic potential to improve glucose metabolism.

2023-12-13 | GSE250078 | GEO

Project description:We investigated the intestinal actions of metformin and imeglimin by transcriptomic profiling. Bulk RNA-seq was performed on intestinal tissues from C57BL/6J mice after single or chronic drug administration, and single-cell RNA-seq was conducted on colon samples after chronic treatment.

2025-09-01 | GSE304061 | GEO

The epigenetic signature of systemic insulin resistance in obese women

Project description:The epigenetic signature of systemic insulin resistance in obese women

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DPP-4 inhibitor sitagliptin improves vascular endothelial function by modulating lncRNA and mRNA expression profiles in obese mouse aortae.

Project description:To investigated the therapeutic mechanism underlying the sitagliptin improves vascular endothelial function in obesity, we performed bioinformatics analyses on the expression profiles of long noncoding RNAs (lncRNAs) and message RNAs (mRNAs) in the aortae from obese mice with or without sitagliptin treatment.

2022-04-19 | GSE200814 | GEO

Factors regulating subcutaneous adipose tissue storage, fibrosis, and inflammation may underlie low systemic rates of fatty acid mobilization in insulin sensitive obese adults

Project description:Although the rate of fatty acid release from adipose tissue into the systemic circulation is very high in most obese adults, some obese adults maintain relatively low rates of fatty acid release, which helps protect them against the development of systemic insulin resistance. The primary aim of this study was to identify factors in adipose tissue that may underlie low vs. high rates of fatty acid mobilization in a relatively homogeneous cohort of obese adults. We obtained subcutaneous abdominal adipose tissue samples from 30 obese adults (BMI: 38±1 kg/m2, age: 30±2 yr) after an overnight fast. We performed microarray analysis on the adiose tissue samples.

2017-03-08 | GSE95777 | GEO

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