cx-4945 and Obesity

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.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Casein Kinase II; Cyclic AMP; Energy Metabolism; Histone Deacetylases; Ion Channels; Male; Mice; Mice, Inbred C57BL; Mitochondrial Proteins; Naphthyridines; Norepinephrine; Obesity; Oxides; Phenazines; Phosphopeptides; Proteomics; Receptors, Adrenergic, beta-3; Signal Transduction; Thermogenesis; Uncoupling Protein 1; Vanadium Compounds