Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet

Despite wide efforts in the last decade, signaling aberrations associated with obesity remain enigmatic. Here, we carried out phosphoproteomic analysis of mouse white adipose tissues (WAT) upon low-fat diet (LFD) and high-fat diet (HFD) to dissect underlying molecular mechanisms of obesity. Of the 7696 phosphopeptides quantified, 191 proteins including various insulin-responsive proteins and metabolic enzymes functioning in lipid homeostasis, exhibited differential phosphorylation with high-fat feeding. Kinase predictions and integrated network analysis identified several deregulated kinase signaling pathways, and suggested possibilities of HFD-induced transcriptional rewiring. Further, functional validation of a novel HFD-responsive site on cytoplasmic acetyl-coA forming ACSS2 (S263) suggested that the phosphorylation is important in regulating insulin signaling and maintaining triglyceride levels. This study represents one of the first comprehensive phosphoproteome data in mouse obesity models, and describes a systems-level approach for identifying deregulated molecular events and potential therapeutic targets in the context of high-fat feeding and adipocyte perturbation.