Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting

Citation:

Maximilian Hatting, Rines, Amy K, Luo, Chi , Tabata, Mitsuhisa , Sharabi, Kfir , Hall, Jessica A, Verdeguer, Francisco , Trautwein, Christian , and Puigserver, Pere . 2017. “Adipose Tissue Clk2 Promotes Energy Expenditure During High-Fat Diet Intermittent Fasting”. Cell Metab, 25, 2, Pp. 428-437. doi:10.1016/j.cmet.2016.12.007.

Abstract:

A promising approach to treating obesity is to increase diet-induced thermogenesis in brown adipose tissue (BAT), but the regulation of this process remains unclear. Here we find that CDC-like kinase 2 (CLK2) is expressed in BAT and upregulated upon refeeding. Mice lacking CLK2 in adipose tissue exhibit exacerbated obesity and decreased energy expenditure during high-fat diet intermittent fasting. Additionally, tissue oxygen consumption and protein levels of UCP1 are reduced in CLK2-deficient BAT. Phosphorylation of CREB, a transcriptional activator of UCP1, is markedly decreased in BAT cells lacking CLK2 due to enhanced CREB dephosphorylation. Mechanistically, CREB dephosphorylation is rescued by the inhibition of PP2A, a phosphatase that targets CREB. Our results suggest that CLK2 is a regulatory component of diet-induced thermogenesis in BAT through increased CREB-dependent expression of UCP1.