TNF-α downregulates CIDEC via MEK/ERK pathway in human adipocytes

Objective: Cell death-inducing DFF45-like effector C (CIDEC) is a lipid droplet-coating protein that promotes triglyceride accumulation and inhibits lipolysis. TNF-α downregulates CIDEC levels to enhance basal lipolysis, whereas CIDEC overexpression could block this effect. This study aimed to investigate the signaling pathway of TNF-α-mediated CIDEC downregulation in human adipocytes.

Methods: First CIDEC expression was detected in adipose tissue of lean and human subjects with obesity. Next, the temporal- and dose-dependent effects of TNF-α on CIDEC expression in human SW872 adipocytes were investigated. Selective inhibitors or RNAi or constitutively active MEK1 mutant was used to suppress or stimulate MEK/ERK cascade. Immunofluorescence and subcellular fractionation technique were used to study PPARγ redistribution after TNF-α treatment. Reporter assay was performed to confirm the direct effects of TNF-α on CIDEC transcription.

Results: CIDEC expression decreased in adipose tissue of subjects with obesity and negatively correlated with adipose TNF-α levels and systemic lipolysis. TNF-α reduced CIDEC expression in vitro, but suppression of MEK/ERK cascade prevented TNF-α-mediated CIDEC downregulation. PPARγ, the transcription factor of CIDEC, was phosphorylated and redistributed by TNF-α in a MEK/ERK-dependent manner. Reporter assay confirmed that TNF-α reduced CIDEC transcription.

Conclusions: TNF-α downregulates CIDEC expression through phosphorylation and nuclear export of PPARγ by MEK/ERK cascade.