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

Maximilian Hatting; Amy K. Rines; Chi Luo; Mitsuhisa Tabata; Kfir Sharabi; Jessica A. Hall; Francisco Verdeguer; Christian Trautwein; Pere Puigserver

doi:10.1016/j.cmet.2016.12.007

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

Maximilian Hatting, Amy K. Rines, Chi Luo, Mitsuhisa Tabata, Kfir Sharabi, Jessica A. Hall, Francisco Verdeguer, Christian Trautwein, Pere Puigserver^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

33 Scopus citations

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.

Original language	American English
Pages (from-to)	428-437
Number of pages	10
Journal	Cell Metabolism
Volume	25
Issue number	2
DOIs	https://doi.org/10.1016/j.cmet.2016.12.007
State	Published - 7 Feb 2017
Externally published	Yes

Bibliographical note

Funding 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.

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

CLK2
PP2A
UCP1
brown fat
diet-induced thermogenesis
high-fat diet
intermittent fasting
p-CREB
refeeding

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.cmet.2016.12.007

Cite this

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title = "Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting",

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.",

keywords = "CLK2, PP2A, UCP1, brown fat, diet-induced thermogenesis, high-fat diet, intermittent fasting, p-CREB, refeeding",

author = "Maximilian Hatting and Rines, {Amy K.} and Chi Luo and Mitsuhisa Tabata and Kfir Sharabi and Hall, {Jessica A.} and Francisco Verdeguer and Christian Trautwein and Pere Puigserver",

note = "Funding Information: This work was supported by the Deutsche Forschungsgemeinschaft (DFG) HA 7246/1-1 and Medizinische Fakult{\"a}t, 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. Publisher Copyright: {\textcopyright} 2017 Elsevier Inc.",

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AU - Hatting, Maximilian

AU - Rines, Amy K.

AU - Luo, Chi

AU - Tabata, Mitsuhisa

AU - Sharabi, Kfir

AU - Hall, Jessica A.

AU - Verdeguer, Francisco

AU - Trautwein, Christian

AU - Puigserver, Pere

N1 - Funding 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. Publisher Copyright: © 2017 Elsevier Inc.

PY - 2017/2/7

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N2 - 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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M3 - Article

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SN - 1550-4131

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JF - Cell Metabolism

IS - 2

ER -

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

Abstract

Bibliographical note

Keywords

UN SDGs

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