Phosphoproteomics Identifies CK2 as a Negative Regulator of Beige Adipocyte Thermogenesis and Energy Expenditure

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Authors:

Shinoda K, Ohyama K, Hasegawa Y, Chang HY, Ogura M, Sato A, Hong H, Hosono T, Sharp LZ, Scheel DW, Graham M, Ishihama Y, Kajimura S.

Journal:

Cell Metabolism

Publication Date:

Tue, 2015-12-01

Institutions:

1UCSF Diabetes Center and Department of Cell and Tissue Biology, University of California, San Francisco, 35 Medical Center Way, San Francisco, CA 94143-0669, USA. 2Department of Molecular and Cellular Bioanalysis, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501, Japan. 3Cardiovascular Group, Department of Antisense Drug Discovery, Isis Pharmaceuticals, Inc., Carlsbad, CA 92008, USA. 4UCSF 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: [email protected].

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.