Mechanism of TNF-α-induced lipolysis in human adipocytes uncovered.

Abstract

Increased lipolysis is linked to obesity, insulin resistance, and type 2 diabetes (1). The complex mechanistic interactions between lipid droplet-associated proteins, lipases, and stimuli that promote lipolysis play a critical role in maintaining a balance between the healthy state versus pathogenic metabolic disease. Tumor necrosis factor (TNF)-α increases lipolysis in adipocytes by regulating lipid droplet-associated proteins and lipases in adipocytes (1, 2). TNF-α reduces the expression of cell death-inducing DFF45-like effector C (CIDEC), also known as fat-specific protein 27, which plays an important role in regulating lipid droplet dynamics, triglyceride accumulation, and lipolysis in adipocytes (1, 2). 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-α-mediated downregulation of CIDEC that ultimately leads to increased basal lipolysis in human adipocytes (5). TNF-α represses CIDEC expression in adipocytes, and this downregulation is critical to enhance lipolysis, as adenoviral maintenance of CIDEC expression blocks TNF-α-mediated lipolysis (6). Previous studies have demonstrated that TNF-α represses peroxisome proliferator-activated receptor (PPAR)-γ expression and activity (1). Since CIDEC is transcriptionally regulated by PPAR-γ (7), does TNF-α downregulate CIDEC expression by affecting PPAR-γ 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-α on lipolysis and found that indeed TNF-α decreases PPAR-γ's transcriptional activity to reduce CIDEC expression, which increases lipolysis (5). Although TNF-α treatment did not affect PPAR-γ expression, mitogen-activated ERK kinase (MEK) and extracellular signal-regulated kinase (ERK)-dependent PPAR-γ phosphorylation were robustly increased. MEK-mediated PPARγ redistribution from nucleus to cytoplasm results in downregulation of PPARγ target genes (8). Furthermore, ERK-dependent inhibitory phosphorylation of PPAR-γ in the nucleus cripples its transcriptional activity (9). The study by Tan et al. highlights MEK/ERK as a central signaling pathway and demonstrates that activation of these signaling cascades is essential for TNF-α-induced CIDEC downregulation, as well as an increase in TNF-α-induced lipolysis (5). Using a systematic approach of siRNA-mediated knockdown and pharmacological inhibitors of MEK/ERK signaling, Tan et al. have shown that repression of these signaling pathways can inhibit TNF-α-induced lipolysis and restore CIDEC expression, thus confirming the direct role of MEK/ERK cascade in TNF-α-induced lipolysis in adipocytes. We are grateful to Dr. Kevin Lee for a helpful discussion on this commentary.