Knockdown of LAP2α inhibits adipogenesis of human adipose‐derived stem cells and ameliorates high‐fat diet‐induced obesity

• Published in: The FASEB journal 2024-05, Vol.38 (10), p.e23664-n/a
• Main Authors: Gu, Hang, Pan, Yuan, Xiao, Han, Zhao, Lijun, Tang, Yiman, Ge, Wenshu
• Format: Article
• Language: English
• Subjects: Adipocytes - metabolism; Adipogenesis; Adipose Tissue - cytology; Adipose Tissue - metabolism; Animals; Cell Differentiation; Cells, Cultured; Diet, High-Fat - adverse effects; DNA-Binding Proteins; Gene Knockdown Techniques; human adipose‐derived stem cells; Humans; lamina‐associated polypeptide 2α; Male; Membrane Proteins; Mesenchymal Stem Cells - metabolism; Mice; Mice, Inbred C57BL; obesity; Obesity - etiology; Obesity - genetics; Obesity - metabolism; STAT3; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202302435RR

Adipogenesis, a pivotal cellular process involving the differentiation of mesenchymal stem cells (MSCs) to mature adipocytes, plays a significant role in various physiological functions. Dysregulation of adipogenesis is implicated in conditions such as obesity. However, the complete molecular understanding of adipogenesis remains elusive. This study aimed to uncover the novel role of lamina‐associated polypeptide 2 alpha (LAP2α) in human adipose‐derived stem cells (hASCs) adipogenesis and its impact on high‐fat diet (HFD)‐induced obesity and associated metabolic disturbances. LAP2α expression was assessed during the adipogenic differentiation of hASCs using RT‐qPCR and western blotting. The functional role of LAP2α in adipogenesis was explored both in vitro and in vivo through loss‐ and gain‐of‐function studies. Moreover, mice with HFD‐induced obesity received lentivirus injection to assess the effect of LAP2α knockdown on fat accumulation. Molecular mechanisms underlying LAP2α in adipogenic differentiation were investigated using RT‐qPCR, Western blotting, immunofluorescence staining, and Oil Red O staining. LAP2α expression was upregulated during hASCs adipogenic differentiation. LAP2α knockdown hindered adipogenesis, while LAP2α overexpression promoted adipogenic differentiation. Notably, LAP2α deficiency resisted HFD‐induced obesity, improved glucose intolerance, mitigated insulin resistance, and prevented fatty liver development. Mechanistically, LAP2α knockdown attenuated signal transducer and activator of transcription 3 (STAT3) activation by reducing the protein level of phosphorylated STAT3. A STAT3 activator (Colivelin) counteracted the negative impact of LAP2α deficiency on hASCs adipogenic differentiation. Taken together, our current study established LAP2α as a crucial regulator of hASCs adipogenic differentiation, unveiling a new therapeutic target for obesity prevention. Our study demonstrated the vital role of LAP2α in regulating adipogenic differentiation of hASCs and preventing obesity. In vitro, LAP2α acted as a positive regulator of hASCs adipogenic differentiation. In vivo, LAP2α deficiency attenuated the development of obesity and its complications. Mechanistically, the knockdown of LAP2α significantly reduced tyrosine phosphorylation of STAT3, and the use of a STAT3 activator (Colivelin) effectively rescued the inhibition of adipogenesis in hASCs caused by LAP2α knockdown.