Sterol Regulatory Element-Binding Protein 2 (SREBP2) Activation after Excess Triglyceride Storage Induces Chemerin in Hypertrophic Adipocytes

• Published in: Endocrinology (Philadelphia) 2011-01, Vol.152 (1), p.26-35
• Main Authors: Bauer, Sabrina, Wanninger, Josef, Schmidhofer, Sandra, Weigert, Johanna, Neumeier, Markus, Dorn, Christoph, Hellerbrand, Claus, Zimara, Nicole, Schäffler, Andreas, Aslanidis, Charalampos, Buechler, Christa
• Format: Article
• Language: English
• Subjects: 3T3-L1 Cells; Adipocytes; Adipocytes - cytology; Adipocytes - metabolism; Adipose tissue; Animal tissues; Animals; Biological and medical sciences; Body fat; Cell activation; Cell differentiation; Chemical synthesis; Chemokines; Chemotactic Factors - genetics; Chemotactic Factors - metabolism; Cholesterol; Diet; Female; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - physiology; High fat diet; Hypertrophy; Intercellular Signaling Peptides and Proteins - genetics; Intercellular Signaling Peptides and Proteins - metabolism; Interleukin-6 - metabolism; Lipopolysaccharides; Lovastatin; Macrophages; Mice; Mice, Inbred C57BL; Molecular modelling; Obesity; Proteins; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sterol Regulatory Element Binding Protein 2 - genetics; Sterol Regulatory Element Binding Protein 2 - metabolism; Sterol regulatory element-binding protein; Sterols; Triglycerides; Triglycerides - metabolism; Tumor Necrosis Factor-alpha; Vertebrates: endocrinology
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2010-1157

Chemerin is an adipokine whose systemic concentration and adipose tissue expression is increased in obesity. Chemerin is highly abundant in adipocytes, yet the molecular mechanisms mediating its further induction in obesity have not been clarified. Adipocyte hypertrophy contributes to dysregulated adipokine synthesis, and we hypothesized that excess loading with free fatty acids (FFA) stimulates chemerin synthesis. Chemerin was expressed in mature adipocytes, and differentiation of 3T3-L1 cells in the presence of FFA further increased its level. TNF and IL-6 were induced by FFA, but concentrations were too low to up-regulate chemerin. Sterol regulatory element-binding protein 2 (SREBP2) was activated in these cells, indicative for cholesterol shortage. Suppression of cholesterol synthesis by lovastatin led to activation of SREBP2 and increased chemerin, and supplementation with mevalonate reversed this effect. Knockdown of SREBP2 reduced basal and FFA-induced chemerin. EMSA confirmed binding of 3T3-L1 adipocyte nuclear proteins to a SREBP site in the chemerin promotor. SREBP2 was activated and chemerin was induced in adipose tissue of mice fed a high-fat diet, and higher systemic levels seem to be derived from adipocytes. Lipopolysaccharide-mediated elevation of chemerin was similarly effective as induction by FFA, indicating that both mechanisms are equally important. Chemokine-like receptor 1 was not altered by the incubations mentioned above, and higher expression in fat of mice fed a high-fat diet may reflect increased number of adipose tissue-resident macrophages in obesity. In conclusion, the current data show that adipocyte hypertrophy and chronic inflammation are equally important in inducing chemerin synthesis. SREBP2, activated upon excess storage of free fatty acids, enhances adipocyte chemerin synthesis.