title: Phosphoprotein network analysis of white adipose tissues unveils deregulated pathways in response to high-fat diet.
abstract: Despite efforts in the last decade, signaling aberrations associated with obesity remain poorly understood. To dissect molecular mechanisms that define this complex metabolic disorder, we carried out global phosphoproteomic analysis of white adipose tissue (WAT) from mice fed on low-fat diet (LFD) and high-fat diet (HFD). We quantified phosphorylation levels on 7696 peptides, and found significant differential phosphorylation levels in 282 phosphosites from 191 proteins, including various insulin-responsive proteins and metabolic enzymes involved in lipid homeostasis in response to high-fat feeding. Kinase-substrate prediction and integrated network analysis of the altered phosphoproteins revealed underlying signaling modulations during HFD-induced obesity, and suggested deregulation of lipogenic and lipolytic pathways. Mutation of the differentially-regulated novel phosphosite on cytoplasmic acetyl-coA forming enzyme ACSS2 (S263A) upon HFD-induced obesity led to accumulation of serum triglycerides and reduced insulin-responsive AKT phosphorylation as compared to wild type ACSS2, thus highlighting its role in obesity. Altogether, our study presents a comprehensive map of adipose tissue phosphoproteome in obesity and reveals many previously unknown candidate phosphorylation sites for future functional investigation.
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Asfa Alli
authors.initials: AA
authors.lastname: Shaik
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Beiying
authors.initials: B
authors.lastname: Qiu
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673, Singapore.
authors.forename: Sheena
authors.initials: S
authors.lastname: Wee
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673, Singapore.|Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, 12 Science Drive 2, Singapore 117549, Singapore.
authors.forename: Hyungwon
authors.initials: H
authors.lastname: Choi
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673, Singapore.|Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, 10 Medical Dr, Singapore 117597, Singapore.
authors.forename: Jayantha
authors.initials: J
authors.lastname: Gunaratne
authors.affiliation: Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, 61 Biopolis Drive, Singapore 138673, Singapore.|Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore.|Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia.
authors.forename: Vinay
authors.initials: V
authors.lastname: Tergaonkar
mesh_terms: D041721:3T3-L1 Cells; D000106:Acetate-CoA Ligase / Q000235:genetics / Q000378:metabolism; D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D051379:Mice; D009154:Mutation; D009765:Obesity / Q000139:chemically induced* / Q000378:metabolism*; D010455:Peptides / Q000737:chemistry; D010750:Phosphoproteins / Q000737:chemistry / Q000378:metabolism*; D060066:Protein Interaction Maps; D040901:Proteomics / Q000379:methods; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism
chemical_list: D010455:Peptides; D010750:Phosphoproteins; D014280:Triglycerides; C000595378:ACSS2 protein, mouse; D000106:Acetate-CoA Ligase