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

Summary A promising approach to treating obesity is to increase diet-induced thermogenesisin 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 CLK2in 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 CLK2due to enhanced CREB dephosphorylation. Mechanistically, CREB dephosphorylationis rescued by the inhibition of PP2A, a phosphatase that targets CREB. Our results suggest that CLK2is a regulatory component of diet-induced thermogenesisin BAT through increased CREB-dependent expression of UCP1.