title: Thrap3 docks on phosphoserine 273 of PPARγ and controls diabetic gene programming.
abstract: Phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at Ser273 by cyclin-dependent kinase 5 (CDK5) in adipose tissue stimulates insulin resistance, but the underlying molecular mechanisms are unclear. We show here that Thrap3 (thyroid hormone receptor-associated protein 3) can directly interact with PPARγ when it is phosphorylated at Ser273, and this interaction controls the diabetic gene programming mediated by the phosphorylation of PPARγ. Knockdown of Thrap3 restores most of the genes dysregulated by CDK5 action on PPARγ in cultured adipocytes. Importantly, reduced expression of Thrap3 in fat tissue by antisense oligonucleotides (ASOs) regulates a specific set of genes, including the key adipokines adiponectin and adipsin, and effectively improves hyperglycemia and insulin resistance in high-fat-fed mice without affecting body weight. These data indicate that Thrap3 plays a crucial role in controlling diabetic gene programming and may provide opportunities for the development of new therapeutics for obesity and type 2 diabetes.
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea; bruce_spiegelman@dfci.harvard.edu janghchoi@unist.ac.kr.
authors.forename: Jang Hyun
authors.initials: JH
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea; bruce_spiegelman@dfci.harvard.edu janghchoi@unist.ac.kr.
authors.forename: Sun-Sil
authors.initials: SS
authors.lastname: Choi
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea;
authors.forename: Eun Sun
authors.initials: ES
authors.lastname: Kim
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Mark P
authors.initials: MP
authors.lastname: Jedrychowski
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea;
authors.forename: Yong Ryoul
authors.initials: YR
authors.lastname: Yang
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea; bruce_spiegelman@dfci.harvard.edu janghchoi@unist.ac.kr.
authors.forename: Hyun-Jun
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan 689-798, Korea;
authors.forename: Pann-Ghill
authors.initials: PG
authors.lastname: Suh
authors.affiliation: Division of Endocrinology, Diabetes, and Hypertension, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Banks
authors.affiliation: Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA;
authors.forename: Steven P
authors.initials: SP
authors.lastname: Gygi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115, USA bruce_spiegelman@dfci.harvard.edu janghchoi@unist.ac.kr.
authors.forename: Bruce M
authors.initials: BM
authors.lastname: Spiegelman
mesh_terms: D016475:3T3 Cells; D054392:Adipokines / Q000235:genetics; D000818:Animals; D002478:Cells, Cultured; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics*; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D047495:PPAR gamma / Q000378:metabolism*; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D011485:Protein Binding; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D054392:Adipokines; D004268:DNA-Binding Proteins; D047495:PPAR gamma; C475774:THRAP3 protein, human; D014157:Transcription Factors; D010768:Phosphoserine; D051360:Cyclin-Dependent Kinase 5
keywords: PPARγ; Thrap3 interaction; energy homeostasis; gene reprogramming; phosphorylation