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

Publication date: Available online 12 January 2017
Source:Cell Metabolism
Author(s): Maximilian Hatting, Amy K. Rines, Chi Luo, Mitsuhisa Tabata, Kfir Sharabi, Jessica A. Hall, Francisco Verdeguer, Christian Trautwein, Pere Puigserver
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.

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Teaser

Diet-induced thermogenesis contributes to energy expenditure in response to overnutrition, presenting a therapeutic target for obesity. Hatting et al. demonstrate that CDC-like kinase 2 (CLK2) is upregulated by feeding and enhances diet-induced thermogenesis in brown adipose tissue, leading to decreased obesity. Mechanistically, CLK2 increases UCP1 through abrogated PP2A-mediated CREB dephosphorylation.


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