title: Phosphoproteomics Identifies CK2 as a Negative Regulator of Beige Adipocyte Thermogenesis and Energy Expenditure.
abstract: Catecholamines promote lipolysis both in brown and white adipocytes, whereas the same stimuli preferentially activate thermogenesis in brown adipocytes. Molecular mechanisms for the adipose-selective activation of thermogenesis remain poorly understood. Here, we employed quantitative phosphoproteomics to map global and temporal phosphorylation profiles in brown, beige, and white adipocytes under β3-adrenenoceptor activation and identified kinases responsible for the adipose-selective phosphorylation profiles. We found that casein kinase2 (CK2) activity is preferentially higher in white adipocytes than brown/beige adipocytes. Genetic or pharmacological blockade of CK2 in white adipocytes activates the thermogenic program in response to cAMP stimuli. Such activation is largely through reduced CK2-mediated phosphorylation of class I HDACs. Notably, inhibition of CK2 promotes beige adipocyte biogenesis and leads to an increase in whole-body energy expenditure and ameliorates diet-induced obesity and insulin resistance. These results indicate that CK2 is a plausible target to rewire the β3-adrenenoceptor signaling cascade that promotes thermogenesis in adipocytes.
authors.affiliation: UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
authors.forename: Kosaku
authors.initials: K
authors.lastname: Shinoda
authors.affiliation: UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
authors.forename: Kana
authors.initials: K
authors.lastname: Ohyama
authors.affiliation: UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Molecular and Cellular Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Hsin-Yi
authors.initials: HY
authors.lastname: Chang
authors.affiliation: Department of Molecular and Cellular Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Mayu
authors.initials: M
authors.lastname: Ogura
authors.affiliation: Department of Molecular and Cellular Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Ayaka
authors.initials: A
authors.lastname: Sato
authors.affiliation: UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
authors.forename: Haemin
authors.initials: H
authors.lastname: Hong
authors.affiliation: UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Hosono
authors.affiliation: UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
authors.forename: Louis Z
authors.initials: LZ
authors.lastname: Sharp
authors.affiliation: UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA.
authors.forename: David W
authors.initials: DW
authors.lastname: Scheel
authors.affiliation: Cardiovascular Group, Department of Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92008, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Graham
authors.affiliation: Department of Molecular and Cellular Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Ishihama
authors.affiliation: UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA. Electronic address: skajimura@diabetes.ucsf.edu.
authors.forename: Shingo
authors.initials: S
authors.lastname: Kajimura
mesh_terms: D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism*; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D047390:Casein Kinase II / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000242:Cyclic AMP / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009287:Naphthyridines / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D009765:Obesity / Q000209:etiology; D010087:Oxides / Q000494:pharmacology; D010619:Phenazines; D010748:Phosphopeptides / Q000032:analysis*; D040901:Proteomics; D022702:Receptors, Adrenergic, beta-3 / Q000378:metabolism; D015398:Signal Transduction; D022722:Thermogenesis / Q000187:drug effects; D000071256:Uncoupling Protein 1; D017968:Vanadium Compounds / Q000494:pharmacology
chemical_list: D007473:Ion Channels; D024101:Mitochondrial Proteins; D009287:Naphthyridines; D010087:Oxides; D010619:Phenazines; D010748:Phosphopeptides; D022702:Receptors, Adrenergic, beta-3; D000071256:Uncoupling Protein 1; D017968:Vanadium Compounds; C581824:vanadium dioxide; C555142:silmitasertib; D000242:Cyclic AMP; D047390:Casein Kinase II; D006655:Histone Deacetylases; D009638:Norepinephrine