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- Author: Michael Stumvoll x
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Department of Internal Medicine III, Interdisciplinary Center for Clinical Research (IZKF) Leipzig, University of Leipzig, 04103 Leipzig, Germany
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Department of Internal Medicine III, Interdisciplinary Center for Clinical Research (IZKF) Leipzig, University of Leipzig, 04103 Leipzig, Germany
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The adipokine tissue inhibitor of metalloproteinase (TIMP)-1 is upregulated when weight is gained and promotes adipose tissue development. In the present study, the effect of insulin resistance-inducing and proinflammatory interleukin (IL)-1β on TIMP-1 gene expression and secretion was investigated in 3T3-L1 adipocytes. Interestingly, protein secretion and mRNA production of TIMP-1 were significantly stimulated by IL-1β. Thus, IL-1β induced TIMP-1 secretion in a dose-dependent manner with maximal 3.5-fold upregulation seen at 0.67 ng/ml IL-1β relative to untreated cells. Furthermore, TIMP-1 mRNA synthesis was significantly stimulated by IL-1β in a dose-dependent fashion with 2.5-fold induction seen at IL-1β concentrations as low as 0.02 ng/ml and maximal 8.1-fold upregulation found at 20 ng/ml effector. Induction of TIMP-1 mRNA was also time dependent with maximal 9.6-fold upregulation detectable after 8 h of IL-1β treatment. Signaling studies suggested that janus kinase 2 is involved in IL-1β-induced TIMP-1 mRNA expression. Taken together, our results demonstrate that the TIMP-1 expression is selectively upregulated by proinflammatory IL-1β, supporting a direct association between insulin resistance, inflammation, and adipose tissue development in obesity.
University of Lübeck, Department of Internal Medicine I, 23538 Lübeck, Germany
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University of Lübeck, Department of Internal Medicine I, 23538 Lübeck, Germany
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University of Lübeck, Department of Internal Medicine I, 23538 Lübeck, Germany
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University of Lübeck, Department of Internal Medicine I, 23538 Lübeck, Germany
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University of Lübeck, Department of Internal Medicine I, 23538 Lübeck, Germany
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University of Lübeck, Department of Internal Medicine I, 23538 Lübeck, Germany
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University of Lübeck, Department of Internal Medicine I, 23538 Lübeck, Germany
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Recently, visfatin was characterized as a novel adipo-cytokine that is upregulated in obesity and exerts insulin-mimetic effects in various tissues. To clarify expression and regulation of this adipocytokine, visfatin mRNA was measured by quantitative real-time reverse transcription-polymerase chain reaction in 3T3-L1 adipocytes during adipogenesis and after treatment with various hormones known to alter insulin sensitivity. Visfatin expression was about 6-fold higher in 3T3-L1 adipocytes in vitro as compared with epididymal fat in vivo and increased during adipogenic conversion more than 3-fold. Interestingly, 100 nM dexamethasone significantly increased visfatin mRNA by almost 1.5-fold. In contrast, 500 ng/ml growth hormone (GH), 10 ng/ml tumor necrosis factor (TNF) α, and 10 μM isoproterenol downregulated visfatin expression by 45%, 36%, and 43% respectively. Insulin did not influence synthesis of this adipocytokine. The effects of dexamethasone, GH, TNFα and isoproterenol were time- and dose-dependent. Furthermore, activation of Gs-protein-coupled pathways by forskolin and cholera toxin was sufficient to significantly downregulate visfatin mRNA. Taken together, our results show a differential regulation of visfatin mRNA by insulin resistance-inducing hormones, supporting the view that this adipo-cytokine might be an interesting novel candidate linking core components of the metabolic syndrome such as obesity and insulin resistance.
Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Medical Department, Leipzig University Medical Center, LIFE Study Center, University of Leipzig, Liebigstrasse 18, 04103 Leipzig, Germany
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Rather than a traditional growth factor, fibroblast growth factor-21 (FGF21) is considered to be a metabolic hormone. In the current study, we investigated serum FGF21 levels in the self-contained population of Sorbs. Serum FGF21 concentrations were quantified by ELISA and correlated with IGF1 as well as metabolic, renal, hepatic, inflammatory, and cardiovascular parameters in 913 Sorbs from Germany. Moreover, human IGF1 protein secretion was investigated in FGF21-stimulated HepG2 cells. Median FGF21 serum concentrations were 2.1-fold higher in subjects with type 2 diabetes mellitus (141.8 ng/l) compared with controls (66.7 ng/l). Furthermore, nondiabetic subjects with FGF21 levels below the detection limit of the ELISA showed a more beneficial metabolic profile compared with subjects with measurable FGF21. Moreover, FGF21 was significantly lower in female compared with male subjects after adjustment for age and BMI. In multiple regression analyses, circulating FGF21 concentrations remained independently and positively associated with gender, systolic blood pressure, triglycerides, and γ glutamyl transferase whereas a negative association was observed with IGF1 in nondiabetic subjects. Notably, FGF21 significantly inhibited IGF1 secretion into HepG2 cell culture supernatants in preliminary in vitro experiments. FGF21 serum concentrations are associated with facets of the metabolic syndrome, hepatocellular function, as well as GH status.
