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 journalArticlepeer-review

38 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 languageAmerican English
Pages (from-to)428-437
Number of pages10
JournalCell Metabolism
Volume25
Issue number2
DOIs
StatePublished - 7 Feb 2017
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2017 Elsevier Inc.

Keywords

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

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