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.
authors.affiliation: 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.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Hatting
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Rines
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Chi
authors.initials: C
authors.lastname: Luo
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mitsuhisa
authors.initials: M
authors.lastname: Tabata
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kfir
authors.initials: K
authors.lastname: Sharabi
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jessica A
authors.initials: JA
authors.lastname: Hall
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute and Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Francisco
authors.initials: F
authors.lastname: Verdeguer
authors.affiliation: RWTH Aachen University, Aachen 52074, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Trautwein
authors.affiliation: 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.
authors.forename: Pere
authors.initials: P
authors.lastname: Puigserver
mesh_terms: D052437:Adipocytes, Brown / Q000378:metabolism; D000273:Adipose Tissue / Q000201:enzymology* / Q000378:metabolism; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D059305:Diet, High-Fat; D018450:Disease Progression; D004734:Energy Metabolism; D005215:Fasting / Q000378:metabolism*; D005247:Feeding Behavior; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology / Q000473:pathology; D009928:Organ Specificity; D010101:Oxygen Consumption; D010766:Phosphorylation; D054648:Protein Phosphatase 2 / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000172:deficiency / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000378:metabolism*; D000071256:Uncoupling Protein 1 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; C066780:Clk dual-specificity kinases; D011505:Protein-Tyrosine Kinases; D017346:Protein Serine-Threonine Kinases; D054648:Protein Phosphatase 2
keywords: CLK2; PP2A; UCP1; brown fat; diet-induced thermogenesis; high-fat diet; intermittent fasting; p-CREB; refeeding