Adipose Tissue CLK2 Promotes Energy Expenditure during High-Fat Diet Intermittent Fasting
Open accessAbstract
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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Recent studies indicate a functional relationship between PP2A-B56 and CLK2 in different physiological and pathological contexts.
“recent studies indicate functional relationship between PP2A-B56 and CLK2 in different physiological and pathological context50,51.”
From Structural mechanism for inhibition of PP2A-B56α and oncogenicity by CIP2A (2023) · cites this paper as [50]
The Introduction identifies a direct functional relationship in liver: CLK2 phosphorylates the PP2A regulatory subunit B56β, affecting PP2A complex assembly and Akt activity. The Results and Discussion also link CLK2 to PP2A-dependent effects in brown adipocytes, but do not establish that B56 mediates those effects or demonstrate a CLK2–B56 relationship across the different contexts claimed. (LLM, conf=0.82)
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References 28 · Cited by 54
- Authors
- Hatting, M., Rines, A. K., Luo, C., Tabata, M., Sharabi, K., Hall, J. A., Verdeguer, F., Trautwein, C., & Puigserver, P.
- Affiliations
- Harvard University (US)
- RWTH Aachen University (DE)
- Corresponding author
- Puigserver, Pere
- Venue
- Cell Metabolism
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 25
- Issue
- 2
- Pages
- 428-437
- ISSN
- 1550-4131 (ISSN-L)
- PMC
- PMC5299049
- OpenAlex
- W2578310144
- Cited by
- 54
- References
- 28
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 9 · 2023: 11 · 2022: 3 · 2021: 8 · 2020: 5 · 2019: 4 · 2018: 3 · 2017: 3
- FWCI
- 3.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell Metabolism (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- RWTH Publications (RWTH Aachen) (submittedVersion)
- Funders
- American Diabetes Association
- National Institute of Diabetes and Digestive and Kidney Diseases (1-R01-DK-089883-01A1, F32 DK102293-03, TR 285/10-1)
- Deutsche Forschungsgemeinschaft (HA 7246/1-1)
- RWTH Aachen University
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- CLK2, brown adipose tissue, diet-induced thermogenesis, energy expenditure, obesity, UCP1, CREB phosphorylation, protein phosphatase 2A, refeeding, tissue oxygen consumption
- MeSH terms
- Uncoupling Protein 1, Adipose Tissue, Animals, Adipose Tissue, Brown, Energy Metabolism, Fasting, Feeding Behavior, Obesity, Organ Specificity, Oxygen Consumption, Phosphorylation, Protein-Tyrosine Kinases, Up-Regulation, Protein Serine-Threonine Kinases, Cyclic AMP Response Element-Binding Protein, Mice, Knockout, Disease Progression, Adipocytes, Brown, Protein Phosphatase 2, Diet, High-Fat
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