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  • 1
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    Online Resource
    Free Fatty Acids Link Metabolism and Regulation of the Insulin-Sensitizing Fibroblast Growth Factor-21
    American Diabetes Association ; 2009
    In:  Diabetes Vol. 58, No. 7 ( 2009-07-01), p. 1532-1538
    Details
    In: Diabetes, American Diabetes Association, Vol. 58, No. 7 ( 2009-07-01), p. 1532-1538
    Abstract: Fibroblast growth factor (FGF)-21 improves insulin sensitivity and lipid metabolism in obese or diabetic animal models, while human studies revealed increased FGF-21 levels in obesity and type 2 diabetes. Given that FGF-21 has been suggested to be a peroxisome proliferator–activator receptor (PPAR) α–dependent regulator of fasting metabolism, we hypothesized that free fatty acids (FFAs), natural agonists of PPARα, might modify FGF-21 levels. RESEARCH DESIGN AND METHODS The effect of fatty acids on FGF-21 was investigated in vitro in HepG2 cells. Within a randomized controlled trial, the effects of elevated FFAs were studied in 21 healthy subjects (13 women and 8 men). Within a clinical trial including 17 individuals, the effect of insulin was analyzed using an hyperinsulinemic-euglycemic clamp and the effect of PPARγ activation was studied subsequently in a rosiglitazone treatment trial over 8 weeks. RESULTS Oleate and linoleate increased FGF-21 expression and secretion in a PPARα-dependent fashion, as demonstrated by small-interfering RNA–induced PPARα knockdown, while palmitate had no effect. In vivo, lipid infusion induced an increase of circulating FGF-21 in humans, and a strong correlation between the change in FGF-21 levels and the change in FFAs was observed. An artificial hyperinsulinemia, which was induced to delineate the potential interaction between elevated FFAs and hyperinsulinemia, revealed that hyperinsulinemia also increased FGF-21 levels in vivo, while rosiglitazone treatment had no effect. CONCLUSIONS The results presented here offer a mechanism explaining the induction of the metabolic regulator FGF-21 in the fasting situation but also in type 2 diabetes and obesity.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db08-1775
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2009
    detail.hit.zdb_id: 1501252-9
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  • 2
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    Insulin facilitates monocyte migration: A possible link to tissue inflammation in insulin-resistance
    Elsevier BV ; 2008
    In:  Biochemical and Biophysical Research Communications Vol. 365, No. 3 ( 2008-01), p. 503-508
    Details
    In: Biochemical and Biophysical Research Communications, Elsevier BV, Vol. 365, No. 3 ( 2008-01), p. 503-508
    Type of Medium: Online Resource
    ISSN: 0006-291X
    URL: Article
    DOI: 10.1016/j.bbrc.2007.11.006
    RVK:
    WA 15000
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2008
    detail.hit.zdb_id: 1461396-7
    SSG: 12
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  • 3
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    The metabolic syndrome: cluster with a self-fulfilling loop?
    Ovid Technologies (Wolters Kluwer Health) ; 2006
    In:  Journal of Hypertension Vol. 24, No. 2 ( 2006-02), p. 257-258
    Details
    In: Journal of Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 24, No. 2 ( 2006-02), p. 257-258
    Type of Medium: Online Resource
    ISSN: 0263-6352
    URL: Article
    DOI: 10.1097/01.hjh.0000202813.79964.4a
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2006
    detail.hit.zdb_id: 2017684-3
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  • 4
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    PPARγ-Activating Angiotensin Type-1 Receptor Blockers Induce Adiponectin
    Ovid Technologies (Wolters Kluwer Health) ; 2005
    In:  Hypertension Vol. 46, No. 1 ( 2005-07), p. 137-143
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 46, No. 1 ( 2005-07), p. 137-143
    Abstract: The adipose-specific protein adiponectin has been recently discovered to improve insulin sensitivity. Angiotensin type-1 receptor (AT1R) blockers (ARBs) reduce the incidence of type 2 diabetes mellitus by mostly unknown molecular mechanisms. To identify new antidiabetic mechanisms of ARBs, we studied the regulation of adiponectin by angiotensin II (Ang II) and different ARBs in murine 3T3-L1 adipocytes and obese Zucker rats. Adiponectin protein expression was markedly stimulated by Ang II (5 nmol/L), which was inhibited by blockade of the AT2R, and further enhanced by the ARB irbesartan. Irbesartan-mediated adiponectin upregulation started beyond the concentrations needed for AT1R blockade and was also present in the absence of Ang II, implicating an AT1R-independent mechanism of action. Recently, certain ARBs (irbesartan, telmisartan) were identified as ligands of the peroxisome proliferator-activated receptor (PPAR)γ. Telmisartan also stimulated adiponectin protein expression, whereas the non-PPARγ-activating ARB eprosartan had no effect. Blockade of PPARγ activation by the PPARγ antagonist GW9662 markedly inhibited irbesartan-induced adiponectin expression. Cognate mRNA levels of adiponectin were not affected by ARBs. Kinetic studies using the protein synthesis inhibitor cycloheximide showed that irbesartan prevented the cellular depletion of adiponectin protein. Finally, administration of irbesartan to obese Zucker rats improved insulin sensitivity and attenuated adiponectin serum depletion. The present study demonstrates that AT2R activation and certain ARBs induce adiponectin in adipocytes, which was associated with an improvement of parameters of insulin sensitivity in vivo. ARB-induced adiponectin stimulation is likely to be mediated via PPARγ activation involving a post-transcriptional mechanism.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/01.HYP.0000168046.19884.6a
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2005
    detail.hit.zdb_id: 2094210-2
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  • 5
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    PPARgamma activation attenuates T-lymphocyte-dependent inflammation of adipose tissue and development of insulin resistance in obese mice
    Springer Science and Business Media LLC ; 2010
    In:  Cardiovascular Diabetology Vol. 9, No. 1 ( 2010-12)
    Details
    In: Cardiovascular Diabetology, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2010-12)
    Abstract: Inflammation of adipose tissue (AT) has been recently accepted as a first step towards obesity-mediated insulin resistance. We could previously show that mice fed with high fat diet (HFD) develop systemic insulin resistance (IR) and glucose intolerance (GI) associated with CD4-positive T-lymphocyte infiltration into visceral AT. These T-lymphocytes, when enriched in AT, participate in the development of fat tissue inflammation and subsequent recruitment of proinflammatory macrophages. The aim of this work was to elucidate the action of the insulin sensitizing PPARgamma on T-lymphocyte infiltration during development of IR, and comparison of the PPARgamma-mediated anti-inflammatory effects of rosiglitazone and telmisartan in diet-induced obesity model (DIO-model) in mice. Methods In order to investigate the molecular mechanisms underlying early development of systemic insulin resistance and glucose intolerance male C57BL/6J mice were fed with high fat diet (HFD) for 10-weeks in parallel to the pharmacological intervention with rosiglitazone, telmisartan, or vehicle. Results Both rosiglitazone and telmisartan were able to reduce T-lymphocyte infiltration into AT analyzed by quantitative analysis of the T-cell marker CD3gamma and the chemokine SDF1alpha. Subsequently, both PPARgamma agonists were able to attenuate macrophage infiltration into AT, measured by the reduction of MCP1 and F4/80 expression. In parallel to the reduction of AT-inflammation, ligand-activated PPARgamma improved diet-induced IR and GI. Conclusion Together the present study demonstrates a close connection between PPARgamma-mediated anti-inflammation in AT and systemic improvement of glucose metabolism identifying T-lymphocytes as one cellular mediator of PPARgamma´s action.
    Type of Medium: Online Resource
    ISSN: 1475-2840
    URL: Article
    DOI: 10.1186/1475-2840-9-64
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2010
    detail.hit.zdb_id: 2093769-6
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  • 6
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    Online Resource
    T-lymphocyte Infiltration in Visceral Adipose Tissue : A Primary Event in Adipose Tissue Inflammation and the Development of Obesity-Mediated Insulin Resistance
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 28, No. 7 ( 2008-07), p. 1304-1310
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 28, No. 7 ( 2008-07), p. 1304-1310
    Abstract: In a mouse model of insulin resistance (IR), high-fat diet induced IR after 5 weeks, which was associated with a marked proinflammatory T-lymphocyte infiltration in visceral adipose tissue, whereas macrophage recruitment was delayed after 10 weeks of diet, suggesting a dissociation of macrophage invasion into adipose tissue and IR initiation.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/ATVBAHA.108.165100
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 1494427-3
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  • 7
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    Histone Deacetylase 6 ( HDAC6 ) Is an Essential Modifier of Glucocorticoid-Induced Hepatic Gluconeogenesis
    American Diabetes Association ; 2012
    In:  Diabetes Vol. 61, No. 2 ( 2012-02-01), p. 513-523
    Details
    In: Diabetes, American Diabetes Association, Vol. 61, No. 2 ( 2012-02-01), p. 513-523
    Abstract: In the current study, we investigated the importance of histone deacetylase (HDAC)6 for glucocorticoid receptor–mediated effects on glucose metabolism and its potential as a therapeutic target for the prevention of glucocorticoid-induced diabetes. Dexamethasone-induced hepatic glucose output and glucocorticoid receptor translocation were analyzed in wild-type (wt) and HDAC6-deficient (HDAC6KO) mice. The effect of the specific HDAC6 inhibitor tubacin was analyzed in vitro. wt and HDAC6KO mice were subjected to 3 weeks’ dexamethasone treatment before analysis of glucose and insulin tolerance. HDAC6KO mice showed impaired dexamethasone-induced hepatic glucocorticoid receptor translocation. Accordingly, dexamethasone-induced expression of a large number of hepatic genes was significantly attenuated in mice lacking HDAC6 and by tubacin in vitro. Glucose output of primary hepatocytes from HDAC6KO mice was diminished. A significant improvement of dexamethasone-induced whole-body glucose intolerance as well as insulin resistance in HDAC6KO mice compared with wt littermates was observed. This study demonstrates that HDAC6 is an essential regulator of hepatic glucocorticoid-stimulated gluconeogenesis and impairment of whole-body glucose metabolism through modification of glucocorticoid receptor nuclear translocation. Selective pharmacological inhibition of HDAC6 may provide a future therapeutic option against the prodiabetogenic actions of glucocorticoids.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/db11-0313
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2012
    detail.hit.zdb_id: 1501252-9
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  • 8
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    Sexual dimorphism in obesity-mediated left ventricular hypertrophy
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Heart and Circulatory Physiology Vol. 305, No. 2 ( 2013-07-15), p. H211-H218
    Details
    In: American Journal of Physiology-Heart and Circulatory Physiology, American Physiological Society, Vol. 305, No. 2 ( 2013-07-15), p. H211-H218
    Abstract: In the present study we investigated the influence of sex difference on the development of left ventricular hypertrophy (LVH) during obesity. Male and female C57BL/6J mice were fed for 15 and 25 wk with a high-fat diet (HFD) or low-fat control diet (LFD). Analysis of body composition, monitoring of body weight (BW), and echocardiographic analysis were performed, as well as analysis of expression of different adipocytokines in epicardial adipose tissue. The increment in left ventricular mass (LVM) after HFD (25 wk) was significantly stronger in male mice compared with female mice [LVM: male, 116.9 ± 2.9 (LFD) vs. 142.2 ± 9.3 mg (HFD); female, 84.3 ± 3.3 (LFD) vs. 93.9 ± 1.7 mg (HFD), P sex 〈 0.01]. In parallel, males developed a higher BW and fat mass after 25 wk HFD than female mice [BW: male, 33 ± 0.9 (LFD) vs. 53 ± 0.8 g (HFD); fat mass: male, 8.8 ± 0.9 (LFD) vs. 22.8 ± 0.7 g (HFD); BW: female, 22.5 ± 0.4 (LFD) vs. 33.7 ± 1.3 g (HFD); fat mass: female, 4.0 ± 0.2 (LFD) vs. 13.2 ± 1.2 g (HFD)] ( P 〈 0.01 for BW+ fat mass female vs. male). The mRNA expression of adipocytokines in epicardial fat after 25 wk of diet showed higher levels of adiponectin (2.8-fold), leptin (4.2-fold), and vaspin (11.9-fold) in male mice compared with female mice ( P 〈 0.05). To identify new adipose-derived molecular mediators of LVH, we further elucidated the cardiac impact of vaspin. Murine primary cardiac fibroblast proliferation was significantly induced by vaspin (1.8-fold, vaspin 1 μg/l, P 〈 0.05 vs. control) compared with 1.9-fold induction by angiotensin II (10 μM). The present study demonstrates a sex-dependent regulation of diet-induced LVH associated with sexual dimorphic expression of adipocytokines in epicardial adipose tissue.
    Type of Medium: Online Resource
    ISSN: 0363-6135 , 1522-1539
    URL: Article
    DOI: 10.1152/ajpheart.00593.2012
    RVK:
    WA 15000
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
    detail.hit.zdb_id: 1477308-9
    SSG: 12
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  • 9
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    AT1-receptor blockade attenuates outward aortic remodeling associated with diet-induced obesity in mice
    Portland Press Ltd. ; 2017
    In:  Clinical Science Vol. 131, No. 15 ( 2017-08-01), p. 1989-2005
    Details
    In: Clinical Science, Portland Press Ltd., Vol. 131, No. 15 ( 2017-08-01), p. 1989-2005
    Abstract: The renin–angiotensin system (RAS) and obesity have been implicated in vascular outward remodeling, including aneurysms, but the precise mechanisms are not yet understood. We investigated the effect of the angiotensin receptor type 1 (AT1-receptor) antagonist telmisartan on aortic outward remodeling in a diet-induced obesity model in mice. C57/Black6J mice were fed either a low-fat diet (LFD) or a high-fat diet (HFD) for 14 weeks. One group of HFD mice was additionally exposed to telmisartan (3 mg/kg per day) for the last 4 weeks. HFD led to aortic outward remodeling, characterized by increased proteolysis, along with structural changes, such as fragmentation of elastic fibers and decreased elastin content. Vascular damage was associated with up-regulation of matrix metalloproteinase (MMP)-2 (MMP-2), MMP-3, MMP-12, cathepsin D, and cathepsin B. HFD aortae exhibited an enhanced inflammatory status, characterized by tumor necrosis factor α (TNF-α) and interleukin-1β (IL-1β) colocalized with adipocytes in the adventitia. HFD resulted in a significant increase in aortic dimensions, evident by ultrasound measurements. Telmisartan abolished aortic dilatation and preserved elastin content. HFD induced enhanced expression of aortic MMP-2, MMP-9, and TNF-α was abrogated by telmisartan. Adventitial proteolytic and inflammatory factors were also examined in samples from human abdominal aneurysms. The expression of TNF-α, IL-1β, and MMP-9 was higher in the adventitial fat of diseased vessels compared with healthy tissues. Finally, adipocytes treated with TNF-α showed enhanced MMP-2, MMP-3, and cathepsin D, which was prevented by telmisartan. Taken together, HFD in mice induced aortic dilatation with up-regulation of matrix degrading and inflammatory pathways similar to those seen in human aortic aneurysmatic tissue. The HFD-induced vascular pathology was reduced by AT1-receptor antagonist telmisartan.
    Type of Medium: Online Resource
    ISSN: 0143-5221 , 1470-8736
    URL: Article
    DOI: 10.1042/CS20170131
    Language: English
    Publisher: Portland Press Ltd.
    Publication Date: 2017
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  • 10
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    Telmisartan Inhibits CD4-Positive Lymphocyte Migration Independent of the Angiotensin Type 1 Receptor via Peroxisome Proliferator-Activated Receptor-γ
    Ovid Technologies (Wolters Kluwer Health) ; 2008
    In:  Hypertension Vol. 51, No. 2 ( 2008-02), p. 259-266
    Details
    In: Hypertension, Ovid Technologies (Wolters Kluwer Health), Vol. 51, No. 2 ( 2008-02), p. 259-266
    Abstract: Migration of CD4-positive lymphocytes into the vessel wall represents an important step in early atherogenesis. Telmisartan is an angiotensin type 1 receptor (AT1R) blocker with peroxisome proliferator-activated receptor (PPAR)-γ–activating properties. The present study examined the effect of telmisartan on CD4-positive cell migration and the role of PPARγ in this context. CD4-positive lymphocytes express both the AT1R and PPARγ. Stimulation of CD4-positive lymphocytes with stromal cell-derived factor (SDF)-1 leads to a 4.1±3.1-fold increase in cell migration. Pretreatment of cells with telmisartan reduces this effect in a concentration-dependent manner to a maximal 1.6±0.7-fold induction at 10 μmol/L of telmisartan ( P 〈 0.01 compared with SDF-1–treated cells; n=22). Three different PPARγ activators, rosiglitazone, pioglitazone, and GW1929, had similar effects, whereas eprosartan, a non-PPARγ–activating AT1R blocker, did not affect chemokine-induced lymphocyte migration. Telmisartan’s effect on CD4-positive lymphocyte migration was mediated through an early inhibition of chemokine-induced phosphatidylinositol 3-kinase activity. Downstream, telmisartan inhibited F-actin formation, as well as intercellular adhesion molecule-3 translocation. Transfection of CD4-positive lymphocytes with PPARγ small interfering RNA abolished telmisartan’s effect on migration, whereas blockade of the AT1R had no such effect. Telmisartan inhibits chemokine-induced CD4-positive cell migration independent of the AT1R via PPARγ. These data provide a novel mechanism to explain how telmisartan modulates lymphocyte activation by its PPARγ-activating properties.
    Type of Medium: Online Resource
    ISSN: 0194-911X , 1524-4563
    URL: Article
    DOI: 10.1161/HYPERTENSIONAHA.107.099028
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2008
    detail.hit.zdb_id: 2094210-2
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