Genetically prolonged beige fat in male mice confers long-lasting metabolic health

Ruifan Wu, Jooman Park, Yanyu Qian, Zuoxiao Shi, Ruoci Hu, Yexian Yuan, Shaolei Xiong, Zilai Wang, Gege Yan, Sang Ging Ong, Qing Song, Zhenyuan Song, Abeer M. Mahmoud, Pingwen Xu, Congcong He, Robert W Arpke, Michael Kyba, Gang Shu, Qingyan Jiang, Yuwei Jiang

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

A potential therapeutic target to curb obesity and diabetes is thermogenic beige adipocytes. However, beige adipocytes quickly transition into white adipocytes upon removing stimuli. Here, we define the critical role of cyclin dependent kinase inhibitor 2A (Cdkn2a) as a molecular pedal for the beige-to-white transition. Beige adipocytes lacking Cdkn2a exhibit prolonged lifespan, and male mice confer long-term metabolic protection from diet-induced obesity, along with enhanced energy expenditure and improved glucose tolerance. Mechanistically, Cdkn2a promotes the expression and activity of beclin 1 (BECN1) by directly binding to its mRNA and its negative regulator BCL2 like 1 (BCL2L1), activating autophagy and accelerating the beige-to-white transition. Reactivating autophagy by pharmacological or genetic methods abolishes beige adipocyte maintenance induced by Cdkn2a ablation. Furthermore, hyperactive BECN1 alone accelerates the beige-to-white transition in mice and human. Notably, both Cdkn2a and Becn1 exhibit striking positive correlations with adiposity. Hence, blocking Cdkn2a-mediated BECN1 activity holds therapeutic potential to sustain beige adipocytes in treating obesity and related metabolic diseases.

Original languageEnglish (US)
Article number2731
JournalNature communications
Volume14
Issue number1
DOIs
StatePublished - Dec 2023

Bibliographical note

Funding Information:
We thank Dr. Lijun Rong for help with manuscript preparation and giving fruitful advice. We thank members in the Y.J. laboratory, especially Nipun Velupally and Meram Mohamed Mahmoud, for mouse genotyping and technical help. We thank Cynthia Rose Adams and Jeanette Purcell for assistance with mouse husbandry, Stefan J. Green and the Research Resources Center for RT-PCR analysis, Dr. Brian Layden and Metabolic Phenotyping Core for analytical and phenotypical mouse measurements, Balaji Ganesh and Flow Cytometry Core facility for FACS and members of the Y.J. laboratory for helpful comments on the manuscript. This work was supported by grants to Y.J. from the National Institute of Diabetes and Digestive and Kidney Disease grant (NIDDK) K01 DK11177, R03 DK127149, R01 DK132398 and Pilot & Feasibility Diabetes Research & Training Center (DRTC) Award (P30DK020595). Cartoons in Figs. a, a, and Supplementary Figs. , , were created with BioRender.com.

Publisher Copyright:
© 2023, The Author(s).

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural

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