2. Academic Validation
  3. Genetically prolonged beige fat in male mice confers long-lasting metabolic health

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

  • Nat Commun. 2023 May 12;14(1):2731. doi: 10.1038/s41467-023-38471-z.
Ruifan Wu # 1 2,  Jooman Park # 1,  Yanyu Qian 1,  Zuoxiao Shi 1 3,  Ruoci Hu 1 3,  Yexian Yuan 1 2,  Shaolei Xiong 4,  Zilai Wang 4,  Gege Yan 5,  Sang-Ging Ong 5 6,  Qing Song 7,  Zhenyuan Song 7,  Abeer M Mahmoud 8,  Pingwen Xu 8,  Congcong He 9,  Robert W Arpke 10,  Michael Kyba 10,  Gang Shu 2,  Qingyan Jiang 2,  Yuwei Jiang 11 12 13
Affiliations

Affiliations

  • 1 Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 2 Guangdong Laboratory of Lingnan Modern Agriculture, Guangdong Province Key Laboratory of Animal Nutritional Regulation and National Engineering Research Center for Breeding Swine Industry, College of Animal Science, South China Agricultural University, Guangzhou, 510642, China.
  • 3 Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 4 Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 5 Department of Pharmacology and Regenerative Medicine, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 6 Division of Cardiology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 7 Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 8 Division of Endocrinology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA.
  • 9 Department of Cell and Developmental Biology, Feinberg School of Medicine, Northwestern University, Chicago, IL, 60611, USA.
  • 10 Lillehei Heart Institute, University of Minnesota, Minneapolis, MN, 55455, USA.
  • 11 Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA. [email protected].
  • 12 Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL, 60612, USA. [email protected].
  • 13 Division of Endocrinology, Department of Medicine, University of Illinois at Chicago, Chicago, IL, 60612, USA. [email protected].
  • # Contributed equally.
PMID: 37169793 DOI: 10.1038/s41467-023-38471-z
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.

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