Abstract
Tumor necrosis factor-α (TNFα) and other ligands of the TNF superfamily are potent regulators of adipose tissue metabolism and play a crucial role in the obesity-induced inflammation of adipose tissue. Adipose tissue expression levels of TRAIL (TNF-related apoptosis-inducing ligand) and its receptor were shown to be upregulated by overfeeding and decreased by fasting in mice. In the present study we aimed to elucidate the impact of TRAIL on adipogenesis. To this end, human Simpson-Golabi-Behmel syndrome (SGBS) preadipocytes as well as stromal-vascular cells isolated from human white adipose tissue were used as model systems. Human recombinant TRAIL inhibited adipogenic differentiation in a dose-dependent manner. It activated the cleavage of caspase-8 and -3, which in turn resulted in a downregulation of the key adipogenic transcription factors C/EBPα, C/EBPδ, and PPARγ. The effect was completely blocked by pharmacological or genetic inhibition of caspases. Taken together we discovered a so far unrecognized function of TRAIL in the regulation of adipogenesis. Targeting the TRAIL/TRAIL receptor system might provide a novel strategy to interfere with adipose tissue homeostasis.
Highlights
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily.[1,2,3] TRAIL interacts with four transmembrane receptors (TRAIL-R1 to TRAIL-R4) and with the soluble receptor osteoprotegerin, all belonging to the TNF receptor (TNFR) superfamily.[2]
This assembly triggers activation of caspase-8 by proximityinduced dimerization and subsequent self-cleavage, which induces further downstream events and apoptosis.[1,4,5]. Besides this classical route of signal transduction, TRAIL can activate alternative, non-canonical pathways. This involves the release of a secondary complex consisting of Fas-associated death domain (FADD), cellular FLICE-like inhibitory protein (cFLIP), caspase-8 or -10, and in addition the adaptor protein TNF receptor type 1-associated death domain (TRADD), receptorinteracting protein kinase 1 (RIPK1), and TNF receptorassociated factor 2 (TRAF2) from the DISC.[6,7,8]
TRAIL belongs to the TNF superfamiliy[2] and other family members were already described to have potent antiadipogenic properties
Summary
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the tumor necrosis factor (TNF) superfamily.[1,2,3] TRAIL interacts with four transmembrane receptors (TRAIL-R1 to TRAIL-R4) and with the soluble receptor osteoprotegerin, all belonging to the TNF receptor (TNFR) superfamily.[2]. This assembly triggers activation of caspase-8 by proximityinduced dimerization and subsequent self-cleavage, which induces further downstream events and apoptosis.[1,4,5] Besides this classical route of signal transduction, TRAIL can activate alternative, non-canonical pathways This involves the release of a secondary complex consisting of FADD, cFLIP, caspase-8 or -10, and in addition the adaptor protein TNF receptor type 1-associated death domain (TRADD), receptorinteracting protein kinase 1 (RIPK1), and TNF receptorassociated factor 2 (TRAF2) from the DISC.[6,7,8] The secondary complex mediates activation of several intracellular signaling cascades including NFκB, Akt, and mitogen-activated protein kinases (MAPK, i.e. p38, JNK, ERK1/2).[8]. The pool of precursor cells and the number of mature adipocytes represent important regulators of adipose tissue homeostasis.[19,20] the aim of the current study was to elucidate the impact of TRAIL on adipogenic differentiation
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