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Mathias Fasshauer, Johannes Klein, Susan Kralisch, Margit Klier, Ulrike Lossner, Matthias Bluher, and Ralf Paschke

A chronic increase in systemic levels of acute-phase reactants contributes to the development of insulin resistance and associated disorders such as cardiovascular disease. Recently, serum amyloid A3 (SAA3) has been characterized as an adipocyte-secreted acute-phase reactant, expression of which is dramatically increased in insulin resistance and obesity. To further clarify expression and regulation of this adipocytokine in fat, SAA3 mRNA was measured by quantitative real-time reverse transcriptase PCR during differentiation of 3T3-L1 adipocytes and after treatment with various hormones known to induce insulin resistance and contribute to atherosclerosis. SAA3 mRNA was dramatically induced up to 77-fold during differentiation of 3T3-L1 preadipocytes. Furthermore, 100 nM dexamethasone and 30 ng/ml interleukin (IL)-6 induced SAA3 mRNA by up to 11- and 4.8-fold, respectively, in a time-dependent fashion with significant stimulation observed at concentrations as low as 10 nM dexamethasone and 1 ng/ml IL-6. In contrast, insulin, isoproterenol and growth hormone did not influence SAA3 synthesis. Inhibitor studies suggested that the positive effect of IL-6 on SAA3 expression is at least in part mediated by Janus kinase 2. Taken together, our results show a differential regulation of SAA3 by glucocorticoids and IL-6 supporting an integrative role of this acute-phase reactant in the pathogenesis of insulin resistance and its link to obesity and cardiovascular disease.

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Sebastian Weise, Susan Kralisch, Grit Sommer, Ulrike Lossner, Matthias Bluher, Michael Stumvoll, and Mathias Fasshauer

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.

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Susan Kralisch, Johannes Klein, Ulrike Lossner, Matthias Bluher, Ralf Paschke, Michael Stumvoll, and Mathias Fasshauer

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.

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Johannes Klein, Sören Westphal, Daniel Kraus, Britta Meier, Nina Perwitz, Volker Ott, Mathias Fasshauer, and H Harald Klein

Metformin is an anti-diabetic drug with anorexigenic properties. The precise cellular mechanisms of its action are not entirely understood. Adipose tissue has recently been recognized as an important endocrine organ that is pivotal for the regulation of insulin resistance and energy homeostasis. Due to its thermogenic capacity brown adipose tissue contributes to the regulation of energy metabolism and is an attractive target tissue for pharmacological approaches to treating insulin resistance and obesity. Leptin is the prototypic adipocyte-derived hormone inducing a negative energy balance. We investigated effects of metformin on adipocyte metabolism, signalling, and leptin secretion in a brown adipocyte model. Metformin acutely stimulated p44/p42 mitogen-activated protein (MAP) kinase in a dose- (3.2-fold at 1 mmol/l, P< 0.05) as well as time-dependent (3.8-fold at 5 min, P< 0.05) manner. This stimulation was highly selective since phosphorylation of intermediates in the stress kinase, janus kinase (JAK)–signal transducer and activator of transcription (STAT), and phosphatidylinositol (PI) 3-kinase signalling pathways such as p38 MAP kinase, STAT3, and Akt was unaltered. Furthermore, chronic metformin treatment for 12 days dose-dependently inhibited leptin secretion by 35% and 75% at 500 μmol/l and 1 mmol/l metformin respectively (P< 0.01). This reduction was not caused by alterations in adipocyte differentiation. Moreover, the impairment in leptin secretion by metformin was reversible within 48 h after removal of the drug. Pharmacological inhibition of p44/p42 MAP kinase prevented the metformin-induced negative effect on leptin secretion. Taken together, our data demonstrate direct acute effects of metformin on adipocyte signalling and endocrine function with robust inhibition of leptin secretion. They suggest a selective molecular mechanism that may contribute to the anorexigenic effect of this antidiabetic compound.

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Susan Kralisch, Anke Tönjes, Kerstin Krause, Judit Richter, Ulrike Lossner, Peter Kovacs, Thomas Ebert, Matthias Blüher, Michael Stumvoll, and Mathias Fasshauer

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.