Leptin Induces Proliferation of Pancreatic β Cell Line MIN6 through Activation of Mitogen-Activated Protein Kinase

Tanabe, Katsuya; Okuya, Shigeru; Tanizawa, Yukio; Matsutani, Akira; Oka, Yoshitomo

doi:10.1006/bbrc.1997.7894

Cited by 122 publications

(93 citation statements)

References 22 publications

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“…Leptin is expressed in developing blood vessels and its receptors are found exclusively on endothelial cells 21 . The expression of leptin is believed to be potentiated in response to ischaemia by activated oncogenes and a variety of cytokines 22 .…”

Section: Discussionmentioning

confidence: 99%

“…Leptin is a potent direct angiogenic factor that stimulates endothelial cell migration and activation in vitro, and angiogenesis in vivo [16][17][18][19][20][21][22] . The observation that leptin mediates angiogenic and mitogenic effects in vitro further implicates an important role for leptin as a mitogenic factor during tissue regeneration in vivo.…”

Section: Introductionmentioning

confidence: 99%

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Burn wound angiogenesis is increased by exogenously administered recombinant leptin in rats

et al. 2008

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Background: Leptin is a potent direct angiogenic factor that stimulates endothelial cell migration and activation in vitro and angiogenesis in vivo. In addition, leptin has been discussed to play an important role in angiogenesis, as it promotes the formation of new blood vessels. Purpose: The effect of exogenously administered leptin on the healing process of a full tissue burn wound model. Methods: Sixty-three Sprague-Dawley male rats were used. Full tissue burn wound was created by electrocautery. The width of the pin was 0.3 cm; its length was 2 cm and was used at the "cut" modulation. Rats were divided into seven groups of nine animals each. Burn wounds were injected with murine recombinant leptin and the rats were sacrificed 3, 7 and 9 days after surgery. Every group had obtained three animals for the three different days of sacrifice. Three different leptin doses of 250 pg/ml, 500 pg/ml and 1000 pg/ml were used in different animal groups (A, B and C). For every one of the three leptin doses used, another animal group was evaluated by using the combined injection of leptin and antileptin (A1, B1, and C1), in order to study the inhibitory effect to the leptin factor. Nine rats were served as controls. These were injected with 0.3 ml water for injection solution and sacrificed at the same time intervals. After sacrifice of the animals, the skin was grossly determined by its appearance, colour and texture. Full thickness burn wounds were dissected for histological examination. A qualitative analysis of angiogenesis in the burn wound was conducted following a standard hematoxylin and eosin stain. The wound tissue samples from each experimental group underwent immunohistochemical evaluation of microvessel density by endothelial cell staining with mouse anti-rat CD 34 monoclonal antibody. Results: The most impressive growth of new blood vessels appeared seven and nine days after treatment with the highest leptin doses. There were no significant differences in microvessel density between the seventh and the ninth postoperative day among different groups treated with leptin. All wounds from the control group, as well as those from animal groups treated with the combined injection of leptin and antileptin did not develop any new vessels. Conclusion: Exogenous administration of recombinant leptin increases early tissue angiogenesis in the burn wound level of an experimental animal model.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Burn wound angiogenesis is increased by exogenously administered recombinant leptin in rats

et al. 2008

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“…But leptin can also use other signaling cascades via JAK activation. Among these are p38 (31), extracellular signal-regulated kinase (ERK1/2) (2,(31)(32)(33)(34)(35)(36), and c-Jun terminal/stressactivated protein kinases (37) of the mitogen-activated protein kinase (MAPK) family members. Furthermore, leptin was found to generate increased amounts of H 2 O 2 in isolated vascular endothelial cells in association with atherogenic processes (37,38).…”

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confidence: 99%

Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells

Cao

Mak

Ren

et al. 2004

Journal of Biological Chemistry

154

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Leptin is recognized as a profibrogenic hormone in the liver, but the mechanisms involved have not been clarified. The tissue inhibitor of metalloproteinase (TIMP)-1, which acts through inhibition of collagen degradation, is synthesized by activated hepatic stellate cells (HSC) in response to fibrogenic substances. The capacity of leptin to induce TIMP-1 and its signaling molecules were investigated in a human HSC cell line, LX-2. Leptin stimulated TIMP-1 protein, mRNA, and promoter activity. JAK1 and -2, as well as STAT3 and -5, were activated. After leptin, there was increased expression of tyrosine 1141-phosphorylated leptin receptor, which may contribute to STAT3 activation. AG 490, a JAK inhibitor, blocked JAK phosphorylation with concomitant inhibition of STAT activation, TIMP-1 mRNA expression, and promoter activity. Leptin also induced an oxidative stress, which was inhibited by AG 490, indicating a JAK mediation process. ERK1/2 MAPK and p38 were activated, which was prevented by catalase, indicating an H 2 O 2 -dependent mechanism. Catalase treatment resulted in total suppression of TIMP-1 mRNA expression and promoter activity. SB203580, a p38 inhibitor, prevented p38 activation and reduced TIMP-1 message half-life with down-regulation of TIMP-1 mRNA. These changes were reproduced by overexpression of the dominant negative p38␣ and p38␤ mutants. PD098059, an ERK1/2 inhibitor, opposed ERK1/2 activation and TIMP-1 promoter activity, leading to TIMP-1 mRNA down-regulation. Thus, leptin has a direct action on liver fibrogenesis by stimulating TIMP-1 production in activated HSC. This process appears to be mediated by the JAK/STAT pathway via the leptin receptor long form and the H 2 O 2 -dependent p38 and ERK1/2 pathways via activated JAK.

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“…Leptin mediates a proliferative response in RINm5F at concentrations of about 100 nM (Islam et al 1997). In MIN-6 cells, this hormone at 1-10 nM increased proliferation as well through activation of the MAPK pathway (Tanabe et al 1997). This proliferative response has been also observed in fetal islet cells and it has been postulated that it might have a role in b-cell mass at birth (Islam et al 2000).…”

Section: Regulation Of B-cell Mass By Leptinmentioning

confidence: 86%

Role of leptin in the pancreatic β-cell: effects and signaling pathways

Marroquí¹,

González²,

Ñeco³

et al. 2012

Journal of Molecular Endocrinology

137

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Leptin plays an important role in the control of food intake, energy expenditure, metabolism, and body weight. This hormone also has a key function in the regulation of glucose homeostasis. Although leptin acts through central and peripheral mechanisms to modulate glucose metabolism, the pancreatic b-cell of the endocrine pancreas is a critical target of leptin actions. Leptin receptors are present in the b-cell, and their activation directly inhibits insulin secretion from these endocrine cells. The effects of leptin on insulin occur also in the long term, since this hormone inhibits insulin gene expression as well. Additionally, b-cell mass can be affected by leptin through changes in proliferation, apoptosis, or cell size. All these different functions in the b-cell are triggered by leptin as a result of the large diversity of signaling pathways that this hormone is able to activate in the endocrine pancreas. Therefore, leptin can participate in glucose homeostasis owing to different levels of modulation of the pancreatic b-cell population. Furthermore, it has been proposed that alterations in this level of regulation could contribute to the impairment of b-cell function in obesity states. In the present review, we will discuss all these issues with special emphasis on the effects and pathways of leptin signaling in the pancreatic b-cell.

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Leptin Induces Proliferation of Pancreatic β Cell Line MIN6 through Activation of Mitogen-Activated Protein Kinase

Cited by 122 publications

References 22 publications

Burn wound angiogenesis is increased by exogenously administered recombinant leptin in rats

Burn wound angiogenesis is increased by exogenously administered recombinant leptin in rats

Leptin Stimulates Tissue Inhibitor of Metalloproteinase-1 in Human Hepatic Stellate Cells

Role of leptin in the pancreatic β-cell: effects and signaling pathways

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