AIMS: Adipocytes play a critical role in energy balance. Growth of fat tissue is 
achieved via an increase in adipocyte mass and the formation of newly 
differentiated adipocytes from precursor cells. Understanding the cellular and 
molecular mechanisms of adipocyte differentiation is crucial for the study of 
obesity- and fat-related diseases. The present study was designed to study 
whether small heterodimer partner-interacting leucine zipper protein (SMILE), a 
novel co-repressor, could regulate differentiation of adipocyte in 3T3-L1 cells.
MATERIALS AND METHODS: Treatment of endoplasmic stress inducers, thapsigargin 
and tunicamycin, inhibited adipocyte differentiation, stimulated Smile mRNA 
expression, and repressed the expression of adiponectin (Adipoq) in 3T3-L1 
pre-adipocyte. Overexpression of SMILE in 3T3-L1 cells decreased the expression 
of the mRNA encoding Adipoq, a major marker of adipocytes, significantly. 
Furthermore, knockdown of SMILE recovered the thapsigargin-mediated repression 
of Adipoq transcription. Co-immunoprecipitation experiments revealed that SMILE 
interacted physically with PPARγ in 3T3-L1 cells. In addition, chromatin 
immunoprecipitation experiments revealed that SMILE suppressed the binding 
affinity of PPARγ for the Adipoq promoter.
KEY FINDINGS: We demonstrate that SMILE controls adipocyte differentiation by 
regulating the transactivity of peroxisome proliferator-activated receptor γ 
(PPARγ).
SIGNIFICANCE: These findings demonstrate that SMILE represses adipocyte 
differentiation by regulating PPARγ transactivity; hence, SMILE is a potential 
regulator of PPARγ-related diseases.