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 and Yuwei Jiang ()
Additional contact information
Ruifan Wu: University of Illinois at Chicago
Jooman Park: University of Illinois at Chicago
Yanyu Qian: University of Illinois at Chicago
Zuoxiao Shi: University of Illinois at Chicago
Ruoci Hu: University of Illinois at Chicago
Yexian Yuan: University of Illinois at Chicago
Shaolei Xiong: University of Illinois at Chicago
Zilai Wang: University of Illinois at Chicago
Gege Yan: University of Illinois at Chicago
Sang-Ging Ong: University of Illinois at Chicago
Zhenyuan Song: University of Illinois at Chicago
Abeer M. Mahmoud: University of Illinois at Chicago
Pingwen Xu: University of Illinois at Chicago
Congcong He: Northwestern University
Robert W. Arpke: University of Minnesota
Michael Kyba: University of Minnesota
Gang Shu: South China Agricultural University
Qingyan Jiang: South China Agricultural University
Yuwei Jiang: University of Illinois at Chicago

Nature Communications, 2023, vol. 14, issue 1, 1-17

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-38471-z

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