The nuclear receptor PPARgamma is considered the central regulator of adipocyte differentiation. Activation of this transcription factor via natural and synthetic agonists leads to the induction of genes involved in fat differentiation and insulin sensitization. Although the mechanisms of PPARgamma's ligand-dependent transcriptional activation have been studied extensively since the discovery of this factor in the early nineties, the ligand-independent function of PPARgamma has not yet been fully elucidated. One of the main focus of the lab is the identification of novel molecules and pathways that can modulate PPARgamma's ligand-independent activity. In order to identify novel PPARgamma modulators we have taken the following approaches: 1) We have analyzed several cofactors candidates that appear to be expressed during adipocyte differentiation and assessed their ability to function as potential transcriptional cofactors for PPARgamma; 2) We have generated several PPARgamma-GST fusion constructs that express distinct domains of PPARgamma. These fusion proteins produced in bacteria have been utilized in biochemical assays to purify potential novel N-terminal interactors. Nuclear extracts obtained from preadipocytes and fully differentiated adipocytes have been analyzed and novel interacting proteins have been identified by mass spectrometry. In addition to the characterization of novel PPARgamma-interacting molecules, we are focusing on the characterization of novel signaling pathways that can enhance differentiation in response to dexamethasone stimuli. For this purpose we have analyzed the pattern of expression of several kinases during different phases of fat differentiation and have identified several potential kinases that could be involved in the regulation of the adipogenic process specifically in response to dexamethasone stimulation. We are currently performing gain-of-function experiments in preadipocytes to assess the ability of these kinases to modulate fat differentiation. In addition we are testing the role of these kinases in vivo, via loss-of-function experiments carried out specifically in adipose tissue. The third focus of this project is the identification of novel factors that control early phases of adipocyte differentiation that precede PPARgamma expression. We are currently testing the role of some candidate transcription factors as early determinants of the adipocyte cell lineage.

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Ma, Xinran; Xu, Lingyan; Mueller, Elisabetta (2016) Forkhead box A3 mediates glucocorticoid receptor function in adipose tissue. Proc Natl Acad Sci U S A 113:3377-82
Mueller, Elisabetta (2016) Browning and Graying: Novel Transcriptional Regulators of Brown and Beige Fat Tissues and Aging. Front Endocrinol (Lausanne) 7:19
Ma, Xinran; Xu, Lingyan; Alberobello, Anna Teresa et al. (2015) Celastrol Protects against Obesity and Metabolic Dysfunction through Activation of a HSF1-PGC1? Transcriptional Axis. Cell Metab :
Ma, Xinran; Xu, Lingyan; Mueller, Elisabetta (2015) Calorie hoarding and thrifting: Foxa3 finds a way. Adipocyte 4:325-8
Adler-Wailes, D C; Alberobello, A T; Ma, X et al. (2015) Analysis of variants and mutations in the human winged helix FOXA3 gene and associations with metabolic traits. Int J Obes (Lond) 39:888-92
Du, Chen; Ma, Xinran; Meruvu, Sunitha et al. (2014) The adipogenic transcriptional cofactor ZNF638 interacts with splicing regulators and influences alternative splicing. J Lipid Res 55:1886-96
Park, Jun Hong; Kang, Hong Jun; Kang, Soo Im et al. (2013) A multifunctional protein, EWS, is essential for early brown fat lineage determination. Dev Cell 26:393-404
Mueller, Elisabetta (2013) Understanding the variegation of fat: Novel regulators of adipocyte differentiation and fat tissue biology. Biochim Biophys Acta :
Meruvu, Sunitha; Hugendubler, Lynne; Mueller, Elisabetta (2011) Regulation of adipocyte differentiation by the zinc finger protein ZNF638. J Biol Chem 286:26516-23
Di Pietro, Natalia; Panel, Valentine; Hayes, Schantel et al. (2010) Serum- and glucocorticoid-inducible kinase 1 (SGK1) regulates adipocyte differentiation via forkhead box O1. Mol Endocrinol 24:370-80

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