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Browning of white adipocytes is considered as a new strategy for the treatment of obesity and its related metabolic diseases. Based on the recent finding that casein kinase-2 (CK2) acts as a negative regulator of browning, new CK2 inhibitors were investigated as potential browning agents. This led to the identification of clomiphene as a candidate. Clomiphene was found to inhibit CK2 activity with an IC of 2.39 μM. Accordingly, clomiphene increased mRNA and protein expression of browning markers, including uncoupling protein-1 (UCP1) in 3T3-L1 white adipocytes and in murine primary adipocytes. In agreement with the increased expression of browning markers, reduced lipid droplets, increased oxygen consumption rates, and mitochondrial biogenesis were detected after clomiphene treatment. Furthermore, phosphorylation of histone deacetylase (HDAC) 1 and 2, downstream mediators of CK2 actions, was decreased by clomiphene. On the other hand, CK2 overexpression diminished clomiphene-induced mitochondrial biogenesis as well as expression of browning markers, suggesting that clomiphene-induced browning is related to its inhibition of CK2. In vivo administration of clomiphene increased the mRNA expression of browning markers in various adipose tissues, accompanied by reduced fat weights and body weights in mice. In summary, these data suggested that clomiphene induced the browning of white adipocytes via CK2 inhibition, which may implicate it as a new anti-obesity drug.
This article was published in the following journal.
Name: European journal of pharmacology
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A casein kinase that was originally described as a monomeric enzyme with a molecular weight of 30-40 kD. Several ISOENZYMES of casein kinase I have been found which are encoded by separate genes. Many of the casein kinase I isoenzymes have been shown to play distinctive roles in intracellular SIGNAL TRANSDUCTION.
A casein kinase I isoenzyme that plays a role in intracellular signaling pathways including the CELL CYCLE, membrane trafficking, and RNA processing. In DROSOPHILA casein kinase Ialpha has been in regulation of Hedghog and Wingless signaling pathways. Multiple isoforms of casein kinase Ialpha exist and are due ALTERNATIVE SPLICING.
A ubiquitous casein kinase that is comprised of two distinct catalytic subunits and dimeric regulatory subunit. Casein kinase II has been shown to phosphorylate a large number of substrates, many of which are proteins involved in the regulation of gene expression.
A casein kinase I isoenzyme with specificity for proteins involved the regulation of the CIRCADIAN RHYTHM.
A casein kinase I isoenzyme that plays a regulatory role in a variety of cellular functions including vesicular transport, CHROMOSOME SEGREGATION; CYTOKINESIS, developmental processes, and the CIRCADIAN RHYTHM.
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