ABSTRACT
The intimate association between obesity and type II diabetes urges for a deeper understanding of adipocyte function. We and others have previously delineated a role for the tumor suppressor p53 in adipocyte biology. Here, we show that mice haploinsufficient for MDM2, a key regulator of p53, in their adipose stores suffer from overt obesity, glucose intolerance, and hepatic steatosis. These mice had decreased levels of circulating palmitoleic acid [non-esterified fatty acid (NEFA) 16:1] concomitant with impaired visceral adipose tissue expression of Scd1 and Ffar4. A similar decrease in Scd and Ffar4 expression was found in in vitro differentiated adipocytes with perturbed MDM2 expression. Lowered MDM2 levels led to nuclear exclusion of the transcriptional cofactors, MORC2 and LIPIN1, and thereby possibly hampered adipocyte function by antagonizing LIPIN1-mediated PPARγ coactivation. Collectively, these data argue for a hitherto unknown interplay between MDM2 and MORC2/LIPIN1 involved in balancing adipocyte function.
Subject(s)
Adipose Tissue, White/metabolism , Insulin Resistance/physiology , Proto-Oncogene Proteins c-mdm2/metabolism , 3T3-L1 Cells , Adipocytes/metabolism , Animals , Diet, High-Fat/adverse effects , Fatty Acids, Monounsaturated/blood , Fatty Liver/genetics , Fatty Liver/metabolism , Female , Gene Regulatory Networks , Glucose Intolerance/genetics , Glucose Intolerance/metabolism , Haploinsufficiency/genetics , Haploinsufficiency/physiology , Insulin Resistance/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Obesity/genetics , Obesity/metabolism , PPAR gamma/metabolism , Phosphatidate Phosphatase , Proto-Oncogene Proteins c-mdm2/deficiency , Proto-Oncogene Proteins c-mdm2/genetics , Transcription Factors/metabolism , Tumor Suppressor Protein p53/metabolismABSTRACT
Motivation: A genome-scale reconstruction of human metabolism, Recon 2, is available but no interface exists to interactively visualize its content integrated with omics data and simulation results. Results: We manually drew a comprehensive map, ReconMap 2.0, that is consistent with the content of Recon 2. We present it within a web interface that allows content query, visualization of custom datasets and submission of feedback to manual curators. Availability and Implementation: ReconMap can be accessed via http://vmh.uni.lu , with network export in a Systems Biology Graphical Notation compliant format released under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. A Constraint-Based Reconstruction and Analysis (COBRA) Toolbox extension to interact with ReconMap is available via https://github.com/opencobra/cobratoolbox . Contact: ronan.mt.fleming@gmail.com.
