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

44 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	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

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

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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.",

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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

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

Abstract

Bibliographical note

Keywords

UN SDGs

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