Ctnnb1/β-catenin inactivation in UCP1-positive adipocytes augments the browning of white adipose tissue

Na Chen; Mingyang Yuan; NingNing Zhang; Maopei Chen; Ruixin Liu; Jiqiu Wang; Peng Lu

doi:10.1016/j.isci.2023.106552

Ctnnb1/β-catenin inactivation in UCP1-positive adipocytes augments the browning of white adipose tissue

iScience. 2023 Apr 1;26(5):106552. doi: 10.1016/j.isci.2023.106552. eCollection 2023 May 19.

Authors

Na Chen^{1

2}, Mingyang Yuan^{1

2}, NingNing Zhang^{1

2}, Maopei Chen³, Ruixin Liu^{1

2}, Jiqiu Wang^{1

2}, Peng Lu⁴

Affiliations

¹ Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
² Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Shanghai 200025, China.
³ Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, China.
⁴ Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Shandong 250021, China.

Abstract

Canonical WNT pathway in mature adipocytes exacerbates obesity. In this study, we constructed UCP1-positive adipocytes-specific Ctnnb1 knockout mice (UBKO) and observed increased "browning" of white adipose tissue (WAT) following cold exposure or CL-316,243 administration compared to controls. UBKO mice also displayed increased energy expenditure. Furthermore, β-catenin (encoded by Ctnnb1) inhibited thermogenic genes expression in differentiated beige adipocytes and repressed Ucp1 expression at transcription level. Transcriptome analysis revealed UBKO mice treated with CL-316,243 had enhanced mitochondrial function and downregulated immune-related genes in epididymal WAT. Improved glucose tolerance and insulin sensitivity were observed in 50-week-old UBKO mice. Public datasets indicated that CTNNB1 expression was inversely correlated with several thermogenic genes expression in human adipose tissue/adipocytes and positively correlated with BMI or waist-hip ratio (WHR). We proposed that intervention of β-catenin in adipocytes could be an effective strategy to enhance energy expenditure and improve age-related metabolic performance.

Keywords: Cell biology; Human metabolism.