2. Academic Validation
  3. SEMA3E promotes beige adipocyte differentiation and thermogenesis via β-catenin signaling in mice

SEMA3E promotes beige adipocyte differentiation and thermogenesis via β-catenin signaling in mice

  • Apoptosis. 2026 Feb 2;31(2):63. doi: 10.1007/s10495-026-02276-4.
Chenxi Xiao # 1 2 3,  Zhenghua Su # 4,  Jialin Zhao # 2,  Yajie Hu 2,  Mengting He 2,  Shenhan Xu 2,  Ruoxue Chen 2,  Jie Xu 2,  Jun Chang 5 6,  Chengshou Lin 7,  Xinhua Liu 8 9,  Wugui Chen 10
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Mindong Hospital Affiliated of Fujian Medical University, No. 89 Heshan Road, Fu'an City, 355000, Fujian, China.
  • 2 Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai, China.
  • 3 The School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China.
  • 4 The School of Pharmacy, Fujian Medical University, Fuzhou, Fujian, China.
  • 5 Department of Orthopaedics, Mindong Hospital Affiliated of Fujian Medical University, No. 89 Heshan Road, Fu'an City, 355000, Fujian, China. [email protected].
  • 6 Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai, China. [email protected].
  • 7 Department of Orthopaedics, Mindong Hospital Affiliated of Fujian Medical University, No. 89 Heshan Road, Fu'an City, 355000, Fujian, China. [email protected].
  • 8 Department of Orthopaedics, Mindong Hospital Affiliated of Fujian Medical University, No. 89 Heshan Road, Fu'an City, 355000, Fujian, China. [email protected].
  • 9 Pharmacophenomics Laboratory, Human Phenome Institute, Fudan University, Shanghai, China. [email protected].
  • 10 Department of Orthopaedics, Mindong Hospital Affiliated of Fujian Medical University, No. 89 Heshan Road, Fu'an City, 355000, Fujian, China. [email protected].
  • # Contributed equally.
PMID: 41627586 DOI: 10.1007/s10495-026-02276-4
Abstract

Beige adipocytes play a key role in non-shivering thermogenesis. SEMA3E, a member of the class 3 semaphorin family, is involved in various pathological processes, but its role in adipocyte differentiation and thermogenesis remains unclear. Here, we found SEMA3E expression increased in inguinal white adipose tissue (iWAT) following cold exposure or β-adrenergic agonist CL316,243 stimulation. In vitro, loss- and gain-of-function experiments revealed that SEMA3E promoted beige adipocyte differentiation and enhanced thermogenic genes expression. In vivo, fat transplantation experiments indicated that SEMA3E promoted adipogenesis. Furthermore, adeno-associated virus (AAV)-mediated SEMA3E knockdown in iWAT impaired thermogenesis in mice exposed to cold or CL316,243. RNA-Seq analysis linked SEMA3E to mitochondrial Oxidative Phosphorylation, and its knockdown reduced mitochondrial respiration by downregulating respiratory chain components expression and lowering mitochondrial oxygen consumption rate. Mechanistically, gene set enrichment analysis suggested SEMA3E regulated beige adipocyte differentiation via the Wnt/β-catenin pathway. SEMA3E knockdown delayed β-catenin degradation, while inhibiting this pathway with IWR-1 rescued the suppressed differentiation and thermogenic genes expression. In conclusion, these findings highlight the crucial role of SEMA3E in beige adipocyte differentiation and thermogenesis.

Keywords

Beige adipocyte; Differentiation; SEMA3E; Thermogenesis; β-catenin.

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