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.
Bibliographical noteFunding Information:
This work was supported by the Deutsche Forschungsgemeinschaft (DFG) HA 7246/1-1 and Medizinische Fakultät, RWTH Aachen University, Rotationstellenprogramm (M.H.); the National Institute of Diabetes and Digestive and Kidney Diseases NRSA F32 DK102293-03 (A.K.R.); DFG TR 285/10-1 (C.T.); and the American Diabetes Association and the NIH/National Institute of Diabetes and Digestive and Kidney Diseases 1-R01-DK-089883-01A1 (P.P.). We would like to thank Joe T. Rodgers for the donation of reagents that were of critical importance to this work and Bruce M. Spiegelman, James Lo, and all the members of the B.M. Spiegelman lab for helpful discussion. A special thanks is given to all members of the P.P. lab: Ajith Thomas and Devin McDonald for technical assistance and Joeva Barrow, Meghan Soustek, Eduardo Balsa, Clint Tavares, Christoph Herbel, Yoonjin Lee, and Henning Fenselau for their scientific and personal support. We also thank Janet Veloz from the BIDMC animal facility for her great support on all animal work.
© 2017 Elsevier Inc.
- brown fat
- diet-induced thermogenesis
- high-fat diet
- intermittent fasting