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

Cell Metab. 2015 Dec 1;22(6):997-1008. doi: 10.1016/j.cmet.2015.09.029. Epub 2015 Nov 8.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / drug effects
  • Adipose Tissue, Brown / metabolism*
  • Adipose Tissue, White / drug effects
  • Adipose Tissue, White / metabolism
  • Animals
  • Casein Kinase II / antagonists & inhibitors
  • Casein Kinase II / genetics
  • Casein Kinase II / metabolism*
  • Cyclic AMP / metabolism
  • Energy Metabolism* / drug effects
  • Histone Deacetylases / chemistry
  • Histone Deacetylases / metabolism
  • Ion Channels / genetics
  • Ion Channels / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondrial Proteins / genetics
  • Mitochondrial Proteins / metabolism
  • Naphthyridines / pharmacology
  • Norepinephrine / pharmacology
  • Obesity / etiology
  • Oxides / pharmacology
  • Phosphopeptides / analysis*
  • Proteomics*
  • Receptors, Adrenergic, beta-3 / metabolism
  • Signal Transduction
  • Thermogenesis / drug effects
  • Uncoupling Protein 1
  • Vanadium Compounds / pharmacology

Substances

  • 5-(3-chlorophenylamino)benzo(c)(2,6)naphthyridine-8-carboxylic acid
  • Ion Channels
  • Mitochondrial Proteins
  • Naphthyridines
  • Oxides
  • Phosphopeptides
  • Receptors, Adrenergic, beta-3
  • Uncoupling Protein 1
  • Vanadium Compounds
  • vanadium dioxide
  • Cyclic AMP
  • Casein Kinase II
  • Histone Deacetylases
  • Norepinephrine