Inhibition of p38MAPK Increases Adipogenesis From Embryonic to Adult Stages

Aouadi, Myriam; Laurent, Kathiane; Prot, Matthieu; Marchand-Brustel, Y. Le; Binétruy, Bernard; Bost, Fréd́eric

doi:10.2337/diabetes.55.02.06.db05-0963

Cited by 160 publications

(128 citation statements)

References 43 publications

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“…p38 has been proposed to act as a negative regulator of adipogenesis, since pharmacological or genetic downregulation of p38 signaling increased the adipogenic yield in atRA-induced cultures of ES cells [21]. We obtained similar results with P19 cells, since atRA + p38 inhibition yielded more adipocytes than atRA alone ( Fig.…”

supporting

confidence: 77%

“…MAPK ERK and p38 have been implicated in mesodermal differentiation, but information is not complete or clear. P38 has an antiadipogenic action [21], while its activity appears to be required in myogenesis [17,[22][23][24][25][26]. However, three recent studies have shown that the use of small concentrations of the p38 inhibitor SB203580 ( £ 10 mM) rather promotes than inhibits cardiomyogenesis [27][28][29].…”

Section: Stem Cells and Developmentmentioning

confidence: 99%

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Differential Effects of Retinoids and Inhibitors of ERK and p38 Signaling on Adipogenic and Myogenic Differentiation of P19 Stem Cells

Bouchard

Paquin

2013

Stem Cells and Development

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All-trans-retinoic acid (atRA) is an essential signaling molecule in embryonic development. It regulates cell differentiation by activating nuclear retinoic acid receptors (RAR) and retinoid-X receptors (RXR), which both control gene expression. In addition, atRA could act in the cytoplasm by modulating the activity of mitogenactivated protein kinases (MAPK) ERK and p38, which also have a role in cell differentiation. AtRA can induce the differentiation of P19 embryonic carcinoma stem cells into adipocytes, cardiomyocytes, and skeletal muscle cells, concurrently, in the same culture. We postulated that combinations of atRA, atRA analogs exhibiting selectivity for RAR or RXR, and inhibitors of ERK and p38 signaling (ERKi and p38i) could be used to favor one mesodermal fate over the others in the P19 model. In a first series of experiments, we replaced atRA by an agonist of RXR (LG100268) or RAR (TTNPB) to preferentially stimulate one group of receptors over the other.LG100268 was as adipogenic and myogenic as atRA, whereas TTNPB strongly induced adipogenesis, but not myogenesis. ERKi enhanced the myogenic action of atRA, and p38i increased both adipogenesis and myogenesis. In a second series of experiments, we combined atRA with an RAR or RXR antagonist (RARatg or RXRatg) to preferentially deactivate each receptor group in turn. The combinations atRA + RXRatg and atRA + RARatg, including or not ERKi, had similar mesodermal actions as atRA. In contrast, there was no myogenesis with atRA + RXRatg + p38i treatment, and there were no myogenesis and no adipogenesis with the atRA + RARatg + p38i combination. Overall, the results indicate that p38 has a role in mesodermal differentiation that depends on the retinoid context. Indeed, p38 in conjunction with RXR is important in myogenesis, and p38 and RAR in adipogenesis. Under the conditions tested, it was possible to stimulate adipogenesis with a block on myogenesis, whereas increased myogenesis was accompanied by adipogenesis.

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supporting

confidence: 77%

Section: Stem Cells and Developmentmentioning

confidence: 99%

Differential Effects of Retinoids and Inhibitors of ERK and p38 Signaling on Adipogenic and Myogenic Differentiation of P19 Stem Cells

Bouchard

Paquin

2013

Stem Cells and Development

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“…Previous studies had led us to anticipate that Mkk3 deficiency would modify the major metabolic events leading to type 2 diabetes. In vitro experiments have shown that p38 activation reduces expression of the glucose transporter GLUT4 [7,36] and suppresses adipogenesis by inhibiting Ppar-γ (also known as Pparg) and c/ebp-β (also known as Cebpb) transcriptional activities [37], suggesting that a deficiency of MKK3-p38 signalling might promote insulin-stimulated glucose uptake and adipose expansion. However, our study showed that Mkk3 deficiency did not affect body weight, insulin and glucose tolerance, plasma insulin or epididymal fat accumulation.…”

Section: Discussionmentioning

confidence: 99%

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

et al. 2008

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Aims/hypothesis Obesity and diabetes are associated with increased intracellular p38 mitogen-activated protein kinase (MAPK) signalling, which may promote tissue inflammation and injury. Activation of p38 MAPK can be induced by either of the immediate upstream kinases, MAP kinase kinase (MKK)3 or MKK6, and recent evidence suggests that MKK3 has non-redundant roles in the pathology attributed to p38 MAPK activation. Therefore, this study examined whether MKK3 signalling influences the development of obesity, type 2 diabetes and diabetic nephropathy. Methods Wild-type and Mkk3 (also known as Map2k3) gene-deficient db/db mice were assessed for the development of obesity, type 2 diabetes and renal injury from 8 to 32 weeks of age. Results Mkk3+/+ db/db and Mkk3 −/− db/db mice developed comparable obesity and were similar in terms of incidence and severity of type 2 diabetes. At 32 weeks, diabetic Mkk3 +/+ db/db mice had increased kidney levels of phospho-p38 and MKK3 protein. In comparison, kidney levels of phospho-p38 in diabetic Mkk3 −/− db/db mice remained normal, despite a fourfold compensatory increase in MKK6 protein levels. The reduced levels of p38 MAPK signalling in the diabetic kidneys of Mkk3 −/− db/ db mice was associated with protection against the following: declining renal function, increasing albuminuria, renal hypertrophy, podocyte loss, mesangial cell activation and glomerular fibrosis. Diabetic Mkk3 −/− db/db mice were also significantly protected from tubular injury and interstitial fibrosis, which was associated with reduced Ccl2 mRNA expression and interstitial macrophage accumulation. Conclusions/interpretation MKK3-p38 MAPK signalling is not required for the development of obesity or type 2 diabetes, but plays a distinct pathogenic role in the progression of diabetic nephropathy in db/db mice.

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“…Cell extracts were prepared using lysis buffer as described previously (Aouadi et al, 2006). Immunoblotting was performed with antibodies against AMPK phosphorylated on Thr172, AMPK, ACC, phospho ACC, S6K1 and phospho S6 K1 (Cell Signaling Technology, Danvers, MA, USA), pRB and cyclin D1 (BD Biosciences Pharmingen, San Jose, CA, USA), E2F1, p27, a1 and a2 AMPK (Santa Cruz Biotechnology, Santa Cruz, CA, USA), a tubulin (Sigma Chemical Co.).…”

Section: Western Blotting Analysismentioning

confidence: 99%

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

et al. 2008

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Metformin is a widely used antidiabetic agent, which regulates glucose homeostasis through inhibition of liver glucose production and an increase in muscle glucose uptake. Recent studies suggest that metformin may reduce the risk of cancer, but its mode of action in cancer remains not elucidated. We investigated the effect of metformin on human prostate cancer cell proliferation in vitro and in vivo. Metformin inhibited the proliferation of DU145, PC-3 and LNCaP cancer cells with a 50% decrease of cell viability and had a modest effect on normal prostate epithelial cell line P69. Metformin did not induce apoptosis but blocked cell cycle in G 0 /G 1 . This blockade was accompanied by a strong decrease of cyclin D1 protein level, pRb phosphorylation and an increase in p27 kip protein expression. Metformin activated the AMP kinase pathway, a fuel sensor signaling pathway. However, inhibition of the AMPK pathway using siRNA against the two catalytic subunits of AMPK did not prevent the antiproliferative effect of metformin in prostate cancer cells. Importantly, oral and intraperitoneal treatment with metformin led to a 50 and 35% reduction of tumor growth, respectively, in mice bearing xenografts of LNCaP. Similar, to the in vitro study, metformin led to a strong reduction of cyclin D1 protein level in tumors providing evidence for a mechanism that may contribute to the antineoplastic effects of metformin suggested by recent epidemiological studies.

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Inhibition of p38MAPK Increases Adipogenesis From Embryonic to Adult Stages

Cited by 160 publications

References 43 publications

Differential Effects of Retinoids and Inhibitors of ERK and p38 Signaling on Adipogenic and Myogenic Differentiation of P19 Stem Cells

Differential Effects of Retinoids and Inhibitors of ERK and p38 Signaling on Adipogenic and Myogenic Differentiation of P19 Stem Cells

Role of MKK3–p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice

The antidiabetic drug metformin exerts an antitumoral effect in vitro and in vivo through a decrease of cyclin D1 level

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