ESPE Abstracts (2014) 82 FC8.3

Identification of Death Ligand TNF-Related Apoptosis-Inducing Ligand as a Potent Mitogen in Human Preadipocytes

Jan-Bernd Funcke, Verena Zoller, Muad Abd El Hay, Klaus-Michael Debatin, Martin Wabitsch & Pamela Fischer-Posovszky

University Medical Center Ulm, Ulm, Germany

Background: Adipose tissue is an important endocrine organ. Its secretion profile is robustly changed in the context of obesity fueling the development of comorbidities such as insulin resistance, diabetes mellitus type 2, and atherosclerosis. We have recently shown that the adipose tissue expression of the death ligand TNF-Related Apoptosis-Inducing Ligand TRAIL and its receptors is upregulated in obesity.

Objective and Hypotheses: In this project, we investigated the effect of TRAIL on the adipose tissue-resident pool of precursor cells, particularly on preadipocyte proliferation.

Method: Simpson-Golabi-Behmel (SGBS) and human primary preadipocytes were used as model systems. Cell proliferation was analysed by microscopic cell counting and 3H-thymidine incorporation. Cell signalling was analysed by western blot.

Results: Stimulation of SGBS preadipocytes with trail resulted in a pronounced, time- and dose-dependent increase in cell proliferation. After 72 h of treatment with 30 ng/ml TRAIL cell proliferation was increased by up to 60%. In comparison, a dose of 300 ng/ml of the well-studied mitogen IGF1 was required to induce a proliferative response proportionate to that of 30 ng/ml TRAIL. The potent mitogenic effect of TRAIL was also present in human primary preadipocytes. Furthermore, the related death ligands FasL and TNFα also showed a considerable mitogenic effect. Albeit no induction of apoptosis was observed in response to TRAIL, a rapid cleavage of caspase-8 and caspase-3 was detected. However, neither chemical inhibition nor genetic ablation of caspases were able to block TRAIL-induced proliferation. Further investigation revealed a delayed and sustained activation of the ERK1/2 cascade. Chemical inhibition of this cascade completely blocked TRAIL-induced proliferation.

Conclusion: We identify TRAIL as a potent mitogen in human preadipocytes. From our data, we conclude that TRAIL functions as a regulator of the adipose tissue-resident pool of precursor cells, possibly modulating adipose tissue development and growth.

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