Mesenchymal Stem Cell-conditioned Medium Alleviates High Fat-induced Hyperglucagonemia via miR-181a-5p and its Target PTEN/AKT Signaling

Abstract Background: Pancreatic α-cells are critical to glucose homeostasis because they release glucagon and stimulate the liver to produce glucose. Dysregulation of α-cells gives rise to fasting and postprandial hyperglycemia in type 2 diabetes mellitus(T2DM). Mesenchymal stem cells (MSCs) or their conditioned medium can improve islet function and enhance insulin sensitivity in target tissues. However, studies showing the direct effect of MSCs on islet α-cell dysfunction are limited. Methods: In this study, we used high-fat diet (HFD)-induced mice and α-cell line exposure to palmitate (PA) to determine the effects of bone marrow-derived MSC-conditioned medium (bmMSC-CM) involved in glucagon secretion. To investigate the potential signaling pathways, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) , AKT and phosphorylated AKT(p-AKT) were assessed by Western blotting.Results: In vivo, bmMSC-CM infusion protected against HFD-induced hyperglycemia and hyperglucagonemia. Consistently, bmMSC-CM decreased PA-induced glucagon secretion in α-cells and isolated islets. Additionally, bmMSC-CM reduced intracellular PTEN expression and rescued AKT signaling. Previous studies and the TargetScan database indicate that miR-181a and its target PTEN play vital roles in ameliorating α-cell dysfunction. We observed that miR-181a-5p is highly expressed in BM-MSCs but prominently lower in αTC1-6 cells. Overexpression or downregulation of miR-181a-5p respectively alleviates or aggravates glucagon secretion in αTC1-6 cells via the PTEN/AKT signaling pathway. Conclusions: Our observations suggest that MSC-secreted miR-181a-5p mitigates glucagon secretion of α-cells by regulating PTEN/AKT signaling. These findings might provide a novel understanding of MSC-based treatment.

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Impact of GPR1 signaling on maternal high-fat feeding and placenta metabolism in mice

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00437.2018 ◽

2019 ◽

Vol 316 (6) ◽

pp. E987-E997 ◽

Cited By ~ 6

Author(s):

Binbin Huang ◽

Chen Huang ◽

Huashan Zhao ◽

Wen Zhu ◽

Baobei Wang ◽

...

Keyword(s):

Biological Effects ◽

Negative Control ◽

Feedback Mechanism ◽

High Fat ◽

Fatty Acid Binding ◽

Maternal Metabolism ◽

Phosphorylated Akt

Chemerin and G protein-coupled receptor 1 (GPR1) are increased in serum and placenta in mice during pregnancy. Interestingly, we observed increased serum chemerin levels and decreased GPR1 expression in placenta of high-fat-diet-fed mice compared with chow-fed mice at gestational day 18. GPR1 protein and gene levels were significantly decreased in gestational diabetes mellitus (GDM) patient placentas. Therefore, we hypothesized that chemerin/GPR1 signaling might participate in the pathogenic mechanism of GDM. We investigated the role of GPR1 in carbohydrate homeostasis during pregnancy using pregnant mice transfected with small interfering RNA for GPR1 or a negative control. GPR1 knockdown exacerbated glucose intolerance, disrupted lipid metabolism, and decreased β-cell proliferation and insulin levels. Glucose transport protein-3 and fatty acid binding protein-4 were downregulated with reducing GPR1 in vivo and in vitro via phosphorylated AKT pathway. Taken together, our findings first demonstrate the expression of GPR1, the characterization of its direct biological effects in humans and mice, as well as the molecular mechanism that indicates the role of GPR1 signaling in maternal metabolism during pregnancy, suggesting a novel feedback mechanism to regulate glucose balance during pregnancy, and GPR1 could be a potential target for the detection and therapy of GDM.

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α-Cell Dysfunctions and Molecular Alterations in Male Insulinopenic Diabetic Mice Are Not Completely Corrected by Insulin

Endocrinology ◽

10.1210/en.2015-1725 ◽

2015 ◽

Vol 157 (2) ◽

pp. 536-547 ◽

Cited By ~ 17

Author(s):

Rodolphe Dusaulcy ◽

Sandra Handgraaf ◽

Mounia Heddad-Masson ◽

Florian Visentin ◽

Christian Vesin ◽

...

Keyword(s):

Cell Differentiation ◽

Insulin Treatment ◽

Cell Function ◽

Cell Mass ◽

Glucagon Secretion ◽

Diabetic Mice ◽

Differentiation Markers ◽

Molecular Alteration ◽

Cell Dysfunction

Abstract Glucagon and α-cell dysfunction are critical in the development of hyperglycemia during diabetes both in humans and rodents. We hypothesized that α-cell dysfunction leading to dysregulated glucagon secretion in diabetes is due to both a lack of insulin and intrinsic defects. To characterize α-cell dysfunction in diabetes, we used glucagon-Venus transgenic male mice and induced insulinopenic hyperglycemia by streptozotocin administration leading to alterations of glucagon secretion. We investigated the in vivo impact of insulinopenic hyperglycemia on glucagon-producing cells using FACS-sorted α-cells from control and diabetic mice. We demonstrate that increased glucagonemia in diabetic mice is mainly due to increases of glucagon release and biosynthesis per cell compared with controls without changes in α-cell mass. We identified genes coding for proteins involved in glucagon biosynthesis and secretion, α-cell differentiation, and potential stress markers such as the glucagon, Arx, MafB, cMaf, Brain4, Foxa1, Foxa3, HNF4α, TCF7L2, Glut1, Sglt2, Cav2.1, Cav2.2, Nav1.7, Kir6.2/Sur1, Pten, IR, NeuroD1, GPR40, and Sumo1 genes, which were abnormally regulated in diabetic mice. Importantly, insulin treatment partially corrected α-cell function and expression of genes coding for proglucagon, or involved in glucagon secretion, glucose transport and insulin signaling but not those coding for cMAF, FOXA1, and α-cell differentiation markers as well as GPR40, NEUROD1, CAV2.1, and SUMO1. Our results indicate that insulinopenic diabetes induce marked α-cell dysfunction and molecular alteration, which are only partially corrected by in vivo insulin treatment.

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Dietary Lycium barbarum Polysaccharide Induces Nrf2/ARE Pathway and Ameliorates Insulin Resistance Induced by High-Fat via Activation of PI3K/AKT Signaling

Oxidative Medicine and Cellular Longevity ◽

10.1155/2014/145641 ◽

2014 ◽

Vol 2014 ◽

pp. 1-10 ◽

Cited By ~ 33

Author(s):

Yi Yang ◽

Wang Li ◽

Yan Li ◽

Qing Wang ◽

Ling Gao ◽

...

Keyword(s):

Insulin Resistance ◽

High Fat Diet ◽

Glycogen Synthase ◽

Akt Signaling ◽

Experimental Models ◽

Related Factor ◽

High Fat ◽

Lycium Barbarum

Lycium barbarum polysaccharide (LBP), an antioxidant from wolfberry, displays the antioxidative and anti-inflammatory effects on experimental models of insulin resistance in vivo. However, the effective mechanism of LBP on high-fat diet-induced insulin resistance is still unknown. The objective of the study was to investigate the mechanism involved in LBP-mediated phosphatidylinositol 3-kinase (PI3K)/AKT/Nrf2 axis against high-fat-induced insulin resistance. HepG2 cells were incubated with LBP for 12 hrs in the presence of palmitate. C57BL/6J mice were fed a high-fat diet supplemented with LBP for 24 weeks. We analyzed the expression of nuclear factor-E2-related factor 2 (Nrf2), Jun N-terminal kinases (JNK), and glycogen synthase kinase 3β (GSK3β) involved in insulin signaling pathway in vivo and in vitro. First, LBP significantly induced phosphorylation of Nrf2 through PI3K/AKT signaling. Second, LBP obviously increased detoxification and antioxidant enzymes expression and reduced reactive oxygen species (ROS) levels via PI3K/AKT/Nrf2 axis. Third, LBP also regulated phosphorylation levels of GSK3β and JNK through PI3K/AKT signaling. Finally, LBP significantly reversed glycolytic and gluconeogenic genes expression via the activation of Nrf2-mediated cytoprotective effects. In summary, LBP is novel antioxidant against insulin resistance induced by high-fat diet via activation of PI3K/AKT/Nrf2 pathway.

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The Role of Phosphoinositide 3-Kinase/Akt Signaling in Low-Dose Mercury-Induced Mouse Pancreatic -Cell Dysfunction In Vitro and In Vivo

Diabetes ◽

10.2337/db06-0029 ◽

2006 ◽

Vol 55 (6) ◽

pp. 1614-1624 ◽

Cited By ~ 75

Author(s):

Y. W. Chen ◽

C. F. Huang ◽

K. S. Tsai ◽

R. S. Yang ◽

C. C. Yen ◽

...

Keyword(s):

Low Dose ◽

Akt Signaling ◽

Pancreatic Cell ◽

Cell Dysfunction ◽

Phosphoinositide 3 Kinase

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Tau Regulates Glioblastoma Progression, 3D Cell Organization, Growth and Migration via the PI3K-AKT Axis

Cancers ◽

10.3390/cancers13225818 ◽

2021 ◽

Vol 13 (22) ◽

pp. 5818

Author(s):

Alessandra Pagano ◽

Gilles Breuzard ◽

Fabrice Parat ◽

Aurélie Tchoghandjian ◽

Dominique Figarella-Branger ◽

...

Keyword(s):

Intracellular Signaling ◽

Xenograft Model ◽

Akt Signaling ◽

Low Grade ◽

Multicellular Spheroids ◽

Phosphorylated Akt ◽

Cell Organization ◽

Tcga Dataset ◽

And Migration

The Microtubule-Associated Protein Tau is expressed in several cancers, including low-grade gliomas and glioblastomas. We have previously shown that Tau is crucial for the 2D motility of several glioblastoma cell lines, including U87-MG cells. Using an RNA interference (shRNA), we tested if Tau contributed to glioblastoma in vivo tumorigenicity and analyzed its function in a 3D model of multicellular spheroids (MCS). Tau depletion significantly increased median mouse survival in an orthotopic glioblastoma xenograft model. This was accompanied by the inhibition of MCS growth and cell evasion, as well as decreased MCS compactness, implying N-cadherin mislocalization. Intracellular Signaling Array analysis revealed a defective activation of the PI3K/AKT pathway in Tau-depleted cells. Such a defect in PI3K/AKT signaling was responsible for reduced MCS growth and cell evasion, as demonstrated by the inhibition of the pathway in control MCS using LY294002 or Perifosine, which did not significantly affect Tau-depleted MCS. Finally, analysis of the glioblastoma TCGA dataset showed a positive correlation between the amount of phosphorylated Akt-Ser473 and the expression of MAPT RNA encoding Tau, underlining the relevance of our findings in glioblastoma disease. We suggest a role for Tau in glioblastoma by controlling 3D cell organization and functions via the PI3K/AKT signaling axis.

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Mesenchymal stem cell-conditioned medium alleviates high fat-induced hyperglucagonemia via miR-181a-5p and its target PTEN/AKT signaling

Molecular and Cellular Endocrinology ◽

10.1016/j.mce.2021.111445 ◽

2021 ◽

pp. 111445

Author(s):

Jia Song ◽

Qin He ◽

Xinghong Guo ◽

Lingshu Wang ◽

Jinbang Wang ◽

...

Keyword(s):

Stem Cell ◽

Mesenchymal Stem Cell ◽

Conditioned Medium ◽

Akt Signaling ◽

High Fat ◽

Cell Conditioned Medium

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Reduced somatostatin signalling leads to hypersecretion of glucagon in mice fed a high fat diet

10.1101/2020.04.07.028258 ◽

2020 ◽

Author(s):

Joely A. Kellard ◽

Nils J. G. Rorsman ◽

Thomas G. Hill ◽

Sarah L Armour ◽

Martijn van der Bunt ◽

...

Keyword(s):

High Fat Diet ◽

Cell Function ◽

Glucagon Secretion ◽

Experimental Models ◽

Alpha Cell ◽

Isolated Islets ◽

Alpha Cells ◽

Plasma Glucagon ◽

High Fat

AbstractElevated plasma glucagon is an early symptom of diabetes, occurring in subjects with impaired glucose regulation. Here we explored alpha-cell function in female mice fed a high fat diet (HFD) – a widely used mouse model of pre-diabetes. In vivo, HFD-fed mice have increased fed plasma glucagon levels that are unaffected by elevation of plasma glucose. To explore the underlying mechanisms, we conducted experiments on isolated islets and in the perfused pancreas. In both experimental models, glucagon secretion under both hypo- and hyperglycaemic conditions was elevated. Because Ca2+ is an important intracellular regulator of glucagon release in alpha-cells, we fed mice expressing the Ca2+ indicator GCaMP3 specifically in alpha-cells the HFD. In mice fed a control (CTL) diet, increasing glucose reduced intracellular Ca2+ ([Ca2+]i) (oscillation frequency and amplitude). This effect was not observed in HFD mice where both the frequency and amplitude of the [Ca2+]i oscillations were higher than in CTL alpha-cells. Given that alpha-cells are under strong paracrine control from neighbouring somatostatin-secreting delta-cells, we hypothesised that this elevation of alpha-cell output was due to a lack of somatostatin (SST) secretion. Indeed, SST secretion in isolated islets from HFD mice was reduced but exogenous SST also failed to suppress glucagon secretion and Ca2+ activity from HFD alpha-cells, in contrast to observations in CTL mice. These findings suggest that reduced delta-cell function, combined with intrinsic changes in alpha-cell sensitivity to somatostatin, accounts for the hyperglucagonaemia in mice fed a HFD.

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