Clomiphene promotes browning of white adipocytes via casein kinase-2 inhibition.

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 IC50 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.