Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPARγ-Ligands

Goetze, Stephan; Bungenstock, Anne; Czupalla, Cornelia; Eilers, Friedrich; Stawowy, Philipp; Kintscher, Ulrich; Spencer-Hänsch, Chantel; Graf, Kristof; Nürnberg, Bernd; Law, Ronald E.; Fleck, Eckart; Gräfe, Michael

doi:10.1161/01.hyp.0000035522.63647.d3

Cited by 164 publications

(119 citation statements)

References 45 publications

(70 reference statements)

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“…Recent studies (45)(46)(47) also suggest that the interaction among the different insulin-sensitive organs may be mediated through interactions between insulin and leptin signaling pathways, which may converge onto AKT and its effectors, such as the forkhead transcription factors and other not-yet-identified targets (48). In the ob͞ob or knockout models, insulin resistance accompanies defects in leptin action in the liver (2-4, 38, 41, 47).…”

Section: Discussionmentioning

confidence: 99%

Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity

Stiles

Wang²,

Stahl³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

391

416

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In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes

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Section: Discussionmentioning

confidence: 99%

Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity

Stiles

Wang²,

Stahl³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

391

416

View full text Add to dashboard Cite

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“…For instance, PPAR-gamma inhibits endothelial cell migration, and plays a key role in influencing the vascular response to atherosclerosis, possibly by reducing the expression of metalloproteinases which are involved in plaque destabilization (51,61). Rosiglitazone treatment decreased the blood serum levels of matrix metalloproteinase (MMP)-9, TNF-alpha and serum amyloid A in diabetic patients with coronary artery disease, and also decreased T-cell activation, thereby curtailing the inflammatory response (87).…”

Section: Anti-inflammatory Effects Of Ppar-gamma Activationmentioning

confidence: 99%

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Kapadia

Yi²,

Vemuganti³

2008

Front Biosci

374

246

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Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors of the nuclear hormone receptor superfamily. The 3 PPAR isoforms (alpha, delta/beta and gamma) are known to control many physiological functions including glucose absorption, lipid balance, and cell growth and differentiation. Of interest, PPAR-gamma activation was recently shown to mitigate the inflammation associated with chronic and acute neurological insults. Particular attention was paid to test the therapeutic potential of PPAR agonists in acute conditions like stroke, spinal cord injury (SCI) and traumatic brain injury (TBI), in which massive inflammation plays a detrimental role. While 15d-prostaglandin J2 (15d PGJ 2 ) is the natural ligand of PPAR-gamma, the thiazolidinediones (TZDs) are potent exogenous agonists. Due to their insulin-sensitizing properties, 2 TZDs rosiglitazone and pioglitazone are currently FDA-approved for type-2 diabetes treatment. Recent studies from our laboratory and other groups have shown that TZDs induce significant neuroprotection in animal models of focal ischemia and SCI by multiple mechanisms. The beneficial actions of TZDs were observed to be both PPAR-gamma-dependent as well as -independent. The major mechanism of TZD-induced neuroprotection seems to be prevention of microglial activation and inflammatory cytokine and chemokine expression. TZDs were also shown to prevent the activation of pro-inflammatory transcription factors at the same time promoting the anti-oxidant mechanisms in the injured CNS. This review article discusses the multiple mechanisms of TZDinduced neuroprotection in various animal models of CNS injury with an emphasis on stroke. KeywordsTranscription Factor; Inflammation; Brain Damage; Nuclear Factor; Cerebral Ischemia; Stroke; Neuroprotection; Review INTRODUCTIONStroke is the leading cause of long-term disability in the adult population worldwide. A variety of pathophysiological processes contribute to the irreversible neuronal injury that eventually results in neurological dysfunction after stroke. The complex nature of these processes involves specific cell types that effect several downstream signalling pathways. In a majority of stroke patients, only a small area of the brain tissue, the ischemic core, is irreversibly damaged. A much larger volume of the brain tissue surrounding the ischemic core, called the penumbra, can potentially recover if treatment is provided in a timely manner (3). Tissue protection and regeneration are tightly regulated by cell growth, survival and cell death signals provided by the cellular microenvironment. Hence, understanding the molecular mechanisms that govern Send correspondence to: Dr. Raghu Vemuganti, Department of Neurological Surgery, K4/8 Mail code CSC 8660, 600 Highland Avenue, Madison, WI 53792, Tel:608-263-4055, Fax:608-263-1728, E-mail: vemugant@neurosurg.wisc.edu. NIH Public Access Author ManuscriptFront Biosci. Author manuscript; available in PMC 2009 August 28. Published in final edited form as:Fr...

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“…Endothelial cell proliferation and migration play critical roles in angiogenesis [19]. Many growth factors have been reported to modulate endothelial cell proliferation, migration and angiogenesis, including those via phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathway to involve eNOS activation [20][21][22][23].…”

Section: Introductionmentioning

confidence: 99%

Low‐energy laser irradiation increases endothelial cell proliferation, migration, and eNOS gene expression possibly via PI3K signal pathway

2008

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Background and Objectives: The purpose of this study, therefore, was to determine the mechanisms by which lowenergy laser irradiation (LELI) may exert some of its angiogenic effects via the PI3 kinase/eNOS signaling pathway and induce endothelial cell migration and neovascularization, an important and necessary part of wound healing. Study Design/Materials and Methods: The possible molecular mechanism of helium-neon (He-Ne) laser irradiation on endothelial cells was proposed. He-Ne laser at 632.5 nm was used to stimulate human umbilical vein endothelial cell (HUVEC), and its effect on cell proliferation, nitric oxide secretion, and cell migration was determined. Results: Irradiation enhanced endothelial nitric oxidase synthase (eNOS) protein expression, and irradiation of less than 0.26 J/cm 2 enhanced eNOS gene expression in HUVEC. The cell migration ability was promoted for HUVEC irradiated with 0.26 J/cm 2 . This agreed with the vinculin protein expression induced by irradiation. In addition, the angiogenesis was promoted. The induced eNOS expression was inhibited by LY294002, indicating that the effect of laser on EC could be attributed to the upregulation of eNOS expression through PI3K pathway at the cellular and molecular levels as a result of the He-Ne laser. Conclusions: The study has shown that LELI increased endothelial cell proliferation, migration, NO secretion, and identified that activation of PI3K/Akt pathway was a critical step for the elevated for eNOS expression upon LELI.

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Leptin Induces Endothelial Cell Migration Through Akt, Which Is Inhibited by PPARγ-Ligands

Cited by 164 publications

References 45 publications

Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity

Liver-specific deletion of negative regulator Pten results in fatty liver and insulin hypersensitivity

Mechanisms of anti-inflammatory and neuroprotective actions of PPAR-gamma agonists

Low‐energy laser irradiation increases endothelial cell proliferation, migration, and eNOS gene expression possibly via PI3K signal pathway

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