Editors' ChoiceMetabolism

Inhibit casein kinase 2 to lose weight

Sci. Signal.  08 Dec 2015:
Vol. 8, Issue 406, pp. ec364
DOI: 10.1126/scisignal.aad9986

Adipose tissue in mammals responds and adapts to nutrient status, exercise, and ambient temperature, which affect the relative amounts of brown adipose tissue (BAT, composed of brown adipocytes) or white adipose tissue (WAT, composed of white adipocytes and a few beige adipocytes) or the number of beige adipocytes within WAT. Brown adipocytes are metabolically active and produce heat (thermogenesis), whereas white adipocytes are fat storage depots. Beige adipocytes are thought to be white adipocytes that have responded to stimuli by becoming more similar to brown adipocytes. Shinoda et al. (see also Enerbäck) employed mass spectrometry–based phosphoproteomics analysis to map norepinephrine-induced temporal changes in protein phosphorylation in differentiated, immortalized brown adipocytes, a white adipocyte cell line (F442A cells), and beige adipocytes (generated from F442A cells). The authors also applied this approach to primary brown adipocytes, inguinal white adipocytes, and beige adipocytes differentiated from inguinal white adipocytes. The phosphorylated proteins clustered by cell type. Analysis of the motifs within the phosphorylated peptides predicted that the activity of the kinase casein kinase 2 (CK2) differed among the three types of adipocytes. In mice fed a high-fat diet compared with mice fed a regular diet, CK2 activity was increased in WAT isolated from the inguinal and epididymal depots, but not in interscapular BAT. RNAi-mediated knockdown of the CK2 α1 subunit or pharmacological inhibition of CK2 by CX-4945 in immortalized white adipocytes derived from inguinal WAT resulted in an increase in the cAMP-induced expression of Ucp1, a gene encoding a mitochondrial uncoupling protein, and of genes encoding various markers of beige and brown adipocytes. Recombinant CK2 increased the phosphorylation of histone deacetylases 1 and 2 (HDAC1 and HDAC2) in protein extracts from differentiated inguinal white adipocytes. Exposure of immortalized white adipocytes to HDAC inhibitors blocked gene expression induced by CK2 inhibition. Compared with untreated mice fed a high-fat diet, mice fed a high-fat diet and subsequently treated with CX-4945 gained less body weight and had smaller epididymal and inguinal WAT depots, and the CX-4945–treated mice had improved systemic glucose homeostasis and decreased hepatic accumulation of lipid droplets and triglycerides. Thus, this study identified CK2 as an inhibitor of the conversion of white adipocytes into more metabolically active beige adipocytes.

K. Shinoda, K. Ohyama, Y. Hasegawa, H.-Y. Chang, M. Ogura, A. Sato, H. Hong, T. Hosono, L. Z. Sharp, D. W. Scheel, M. Graham, Y. Ishihama, S. Kajimura, Phosphoproteomics identifies CK2 as a negative regulator of beige adipocyte thermogenesis and energy expenditure. Cell Metab. 22, 997–1008 (2015). [PubMed]

S. Enerbäck, Casein kinase 2—A kinase that inhibits brown fat formation. Cell Metab. 22, 958–959 (2015). [PubMed]