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Cited by 12Wnt/β-catenin signaling in development and cancerLipid metabolism and biosynthesisLipid metabolism and disorders

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Wnt/Wingless signaling promotes lipid mobilization through signal-induced transcriptional repression

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Liu, Mengmeng, Hemba-Waduge, Rajitha-Udakara-Sampath, Li, Xiao, Huang, Xiahe, Liu, Tzu-Hao, Han, Xianlin, Wang, Yingchun, Ji, Jun-Yuan·2024·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2322066121PMC PMC11252803

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Abstract

The Wnt/Wingless signaling pathway plays critical roles in metazoan development and energy metabolism, but its role in regulating lipid homeostasis remains not fully understood. Here, we report that the activation of canonical Wnt/Wg signaling promotes lipolysis while concurrently inhibiting lipogenesis and fatty acid β-oxidation in both larval and adult adipocytes, as well as cultured S2R+ cells, in Drosophila . Using RNA-sequencing and CUT&RUN (Cleavage Under Targets & Release Using Nuclease) assays, we identified a set of Wnt target genes responsible for intracellular lipid homeostasis. Notably, active Wnt signaling directly represses the transcription of these genes, resulting in decreased de novo lipogenesis and fatty acid β-oxidation, but increased lipolysis. These changes lead to elevated free fatty acids and reduced triglyceride (TG) accumulation in adipocytes with active Wnt signaling. Conversely, downregulation of Wnt signaling in the fat body promotes TG accumulation in both larval and adult adipocytes. The attenuation of Wnt signaling also increases the expression of specific lipid metabolism-related genes in larval adipocytes, wing discs, and adult intestines. Taken together, these findings suggest that Wnt signaling-induced transcriptional repression plays an important role in regulating lipid homeostasis by enhancing lipolysis while simultaneously suppressing lipogenesis and fatty acid β-oxidation.

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Metadata

Authors
Liu, M., Hemba-Waduge, R.-U.-S., Li, X., Huang, X., Liu, T.-H., Han, X., Wang, Y., & Ji, J.-Y.
Affiliations
  • Tulane University (US)
  • Princeton University (US)
  • Chinese Academy of Sciences (CN)
  • The University of Texas at San Antonio Health Science Center (US)
Corresponding author
  • Liu, Mengmeng
  • Hemba-Waduge, Rajitha-Udakara-Sampath
  • Ji, Jun-Yuan
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2024-07-05
Volume
121
Issue
28
Pages
e2322066121-e2322066121
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2322066121
PMC
PMC11252803
OpenAlex
W4400351855
Cited by
12
References
4
Citations by year
2026: 5 · 2025: 5 · 2024: 2
FWCI
1.63
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • HHS | NIH | National Institute of General Medical Sciences (GM129266)
  • HHS | NIH | National Institute on Aging (P30 AG013319, AG044271)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
Keywords
Wnt/β-catenin signaling, lipid homeostasis, lipolysis, de novo lipogenesis, fatty acid beta-oxidation, transcriptional repression, adipocytes, fat body, triglyceride accumulation, free fatty acids, Drosophila, energy metabolism, Wnt target genes
MeSH terms
Animals, Drosophila melanogaster, Homeostasis, Larva, Lipid Mobilization, Lipolysis, Transcription, Genetic, Triglycerides, Adipocytes, Drosophila Proteins, Lipogenesis, Lipid Metabolism, Wnt1 Protein, Wnt Signaling Pathway

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