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Cell Metab. 2017 Feb 7;25(2):428-437. doi: 10.1016/j.cmet.2016.12.007. Epub 2017 Jan 12.

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

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA; RWTH Aachen University, Aachen 52074, Germany.
2
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
3
RWTH Aachen University, Aachen 52074, Germany.
4
Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: pere_puigserver@dfci.harvard.edu.

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

PMID:
28089567
PMCID:
PMC5299049
DOI:
10.1016/j.cmet.2016.12.007
[Indexed for MEDLINE]
Free PMC Article

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