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

Abstract

Objective: Cell death-inducing DFF45-like effector C (CIDEC) is a lipid droplet-coating protein that promotes triglyceride accumulation and inhibits lipolysis. TNF-a downregulates CIDEC levels to enhance basal lipolysis, whereas CIDEC overexpression could block this effect. This study aimed to investigate the signaling pathway of TNF-a-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-a 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 PPARc redistribution after TNF-a treatment. Reporter assay was performed to confirm the direct effects of TNF-a on CIDEC transcription. Results: CIDEC expression decreased in adipose tissue of subjects with obesity and negatively correlated with adipose TNF-a levels and systemic lipolysis. TNF-a reduced CIDEC expression in vitro, but suppression of MEK/ERK cascade prevented TNF-a-mediated CIDEC downregulation. PPARc, the transcription factor of CIDEC, was phosphorylated and redistributed by TNF-a in a MEK/ERK-dependent manner. Reporter assay confirmed that TNF-a reduced CIDEC transcription. Conclusions: TNF-a downregulates CIDEC expression through phosphorylation and nuclear export of PPARc by MEK/ERK cascade.

TNF‐α Upregulates IKKε Expression via the Lin28B/let‐7a Pathway to Induce Catecholamine Resistance in Adipocytes

“…More than 90% of 3T3‐L1 preadipocytes were fully differentiated into adipocytes with multiple lipid droplets after a 12‐day culture, following the protocol as previously described (Figure A). Consistent with our previous findings and those of several other studies , treatment with TNF‐α for 24 hours dose dependently increased basal lipolysis in adipocytes. 3T3‐L1 adipocytes were treated with various concentrations of TNF‐α for 24 hours followed by isoproterenol treatment for 90 minutes.…”

Single nucleotide polymorphisms in CIDEC gene are associated with metabolic syndrome components risks and antihypertensive drug efficacy

“…As a consequence, excessive free fatty acids (FFAs) and unbalanced cluster of adipokines would be released into circulation. Indeed, CIDEC expression in white adipose tissue was reported to be negatively correlated with blood FFAs concentration [12]. Excessive FFAs [23] and dysregulated adipokines network [24] disrupt glucose and lipid homeostasis by triggering and accelerating systemic lipotoxicity and insulin resistance, which may be possible mechanisms of the elevation of blood glucose and triglyceride (Supplementary Figure 1).…”

“…Human data showed the amount of CIDEC mRNA in white adipose tissue was decreased in obesity [12, 13], and positively correlated with insulin sensitivity [12–14]. In addition, a case with familial partial lipodystrophy 5 was reported to harbor a nonsense mutation at the sixth exon of CIDEC [15].…”

Mechanism of TNF‐α‐induced lipolysis in human adipocytes uncovered

“…Recent studies have showed that CIDEC regulates lipolysis in human adipocytes by regulating catalytic capacity (3), as well as transcription of adipose triglyceride lipase (4). The study by Tan et al published in this issue of Obesity provides a detailed mechanism for TNF-a-mediated downregulation of CIDEC that ultimately leads to increased basal lipolysis in human adipocytes (5).…”

“…Since CIDEC is transcriptionally regulated by PPAR-c (7), does TNF-a downregulate CIDEC expression by affecting PPAR-c expression and/or activity? Utilizing a commercially available SW872-cultured human adipocyte model system, Tan et al systematically studied the mechanism of action of TNF-a on lipolysis and found that indeed TNF-a decreases PPAR-c's transcriptional activity to reduce CIDEC expression, which increases lipolysis (5). Although TNF-a treatment did not affect PPAR-c expression, mitogen-activated ERK kinase (MEK) and extracellular signalregulated kinase (ERK)-dependent PPAR-c phosphorylation were robustly increased.…”