The antiobesity factor WDTC1 suppresses adipogenesis via the CRL4WDTC1 E3 ligase

Area of Science:

• Biochemistry
• Molecular Biology
• Cell Biology

Background:

• WDTC1/Adp is an evolutionarily conserved protein that suppresses lipid accumulation.
• Reduced WDTC1 expression is linked to obesity in both mice and humans.
• The precise cellular function of WDTC1 remains largely unknown.

Purpose of the Study:

• To elucidate the cellular function of WDTC1.
• To investigate the role of WDTC1 in adipogenesis and lipid accumulation.
• To determine the biochemical activity of WDTC1 within cellular complexes.

Main Methods:

• Utilized 3T3-L1 cell culture to model adipogenesis.
• Investigated WDTC1's role as a component of a DDB1-CUL4-ROC1 (CRL4) E3 ligase complex.
• Assessed the impact of disrupting WDTC1-DDB1 interaction on adipogenic gene expression and triglyceride accumulation.
• Examined the effect of the CRL4(WDTC1) complex on histone H2AK119 monoubiquitylation.

Main Results:

• WDTC1 was identified as a component of the CRL4 E3 ligase complex.
• Disruption of the WDTC1-DDB1 interaction abrogated WDTC1's ability to suppress adipogenesis.
• Impaired WDTC1 function led to increased triglyceride accumulation and altered adipogenic gene expression.
• The CRL4(WDTC1) complex was shown to promote histone H2AK119 monoubiquitylation, indicating a role in transcriptional repression.

Conclusions:

• WDTC1 functions biochemically as part of a CRL4 E3 ligase complex.
• This complex plays a critical role in suppressing fat accumulation during adipogenesis via transcriptional repression.
• The findings extend the known functions of CRL4 complexes to include the regulation of lipid metabolism and obesity suppression.