Molecular Mechanisms of Adipogenesis and Adipocyte Biology : Possible role of MKPs and STAMPs
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AbstractAdipogenesis is the developmental process that upon appropriate stimuli differentiates progenitor cells into specialized fat storing adipocytes. We studied this process and the potential involvement of two different protein families; Six Transmembrane Proteins of Prostate (STAMP, also names STEAP) and the MAP kinase phosphatases (MKPs). The STAMP protein family consists of four members, STAMP1-3 and STEAP. Little is known about the role of this family in human adipogenesis. In order to address this we made use of adipose-derived stem cells (ASCs) that can be isolated in high quantities from human lipoaspirate material and which can be differentiated into all mesoderm derived cells. Differentiation of ASCs into adipocytes dramatically increased STAMP2 expression and significantly increased STEAP without affecting STAMP1 and STAMP3 expression. Reduced expression of STAMP2 by RNA interference reduced the ability of ASCs to differentiate into adipocytes, decreased expression of genes involved in lipogenesis, and increased expression of an enzyme involved in β-oxidation. This suggests that STAMP2 could be an inducer of adipogenesis and lipogenesis in humans. Our work also focused on MKPs, which consist of proteins that inhibit the kinase activity of the MAP Kinases (MAPKs) that have previously been implicated in adipogenesis. We comprehensively analyzed the expression levels of MKPs during adipogenesis of the murine 3T3-L1 cells and present data regarding MKP-5, MKP-6, VHR, and VH5. All MKPs we studied had a similar expression profile during adipogenesis where levels were high in dividing pre-adipocytes but dropped significantly upon cells reaching confluency. After induction of adipogenesis, MKP levels remained low during the beginning phases of differentiation whereas levels increased and reached their maximum at day 8. We also investigated the expression levels in mouse models of diet-induced or genetic obesity and found that there was significant deregulation of MKPs in subcutaneous fat and livers of obese mice. The final area of focus in this thesis was inflammation and endoplasmic reticulum (ER) stress, which are hallmarks of metabolic disease. Previously, genetic removal of STAMP2 from mice was shown to increase inflammation and induce metabolic disease in lean mice on a regular diet. We induced ER stress in adipocytes and found short term ER stress to delocalize STAMP2 from the plasma membrane to intracellular compartments, while chronic ER stress completely extinguished STAMP2 expression. This was shown to be a consequence of disrupted C/EBPα binding to the STAMP2 promoter. These data suggest that downregulation of STAMP2 expression is one mechanism of ER stress-mediated metabolic disease. Overall, the data presented in this thesis contribute to the understanding of the molecular details of adipogenesis, which may be relevant in tackling issues related to obesity and related disorders.
List of papers
|PAPER I: Kathryn E. Wellen, Raquel Fucho, Margaret F. Gregor, Masato Furuhashi, Carlos Morgan, Torstein Lindstad, Eric Vaillancourt, Cem Z. Gorgun, Fahri Saatcioglu and Gökhan S. Hotamisligil (2007) Coordinated Regulation of Nutrient and Inflammatory Responses by STAMP2 Is Essential for Metabolic Homeostasis. Cell, 129(3): 537-548, 2007. https://doi.org/10.1016/j.cell.2007.02.049|