Meeting abstract
Polymorphisms in TMEM18 are associated with obesity in children and adults. We have reported previously that TMEM18 is a regulator of human adipogenesis in vitro [1]. The aim of this study was to investigate the role of TMEM18 during adipose tissue (AT) accumulation in vivo. For this, we used the zebrafish as an in vivo model for AT development. In addition, we analysed TMEM18 expression in whole AT samples, isolated adipocytes and cells of the stroma-vascular fraction (SVF) from lean and obese children of our Leipzig Childhood AT cohort [2], and addressed associations with PPARG expression and obesity-related parameters.
Using whole mount in situ hybridisation on 9 day old zebrafish larvae, we showed co-expression of tmem18 and pparg in a visceral region where also first adipocytes are detectable by Nile red staining. Morpholino-mediated inhibition of tmem18 expression resulted in a reduction in the number of visceral adipocytes but did not affect zebrafish development per se. There was no effect of tmem18 knockdown on eating behaviour suggesting that the inhibition of adipocyte formation was not mediated by a central effect. Tmem18-mediated inhibition of adipogenesis was accompanied by a significant down-regulation in pparg expression. Using luciferase reporter assays in 3T3-L1 cells, we detected a significant activation of the PPARG promoter in presence of Tmem18 indicating that Tmem18 is an upstream regulator of PPARG signalling. In line with these data, TMEM18 expression correlated with PPARG expression in whole AT and isolated adipocytes but not in SVF cells of children included in our Leipzig AT cohort. Similar to PPARG, TMEM18 expression was down-regulated in adipocytes of obese children compared to lean children and correlated with adipocyte diameter, macrophage infiltration, serum adiponectin levels and HOMA-IR as a measure of insulin resistance.
Our findings may indicate a potential role of TMEM18 as a regulator of PPARG signaling during adipogenesis in vivo.
References
Bernhard F, Landgraf K, Kloting N, Berthold A, Buttner P, Friebe D, et al.: Functional relevance of genes implicated by obesity genome-wide association study signals for human adipocyte biology. Diabetologia 2013,56(2):311–322. 10.1007/s00125-012-2773-0
Landgraf K, Rockstroh D, Wagner IV, Weise S, Tauscher R, Schwarze JT, et al.: Evidence of early alterations in adipose tissue biology and function and its association with obesity-related inflammation and insulin resistance in children. Diabetes 2015,64(4):1249–1261. 10.2337/db14-0744
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Landgraf, K., Schwartze, J., Rockstroh, D. et al. TMEM18 is a regulator of adipogenesis and involved in PPARG signalling in vivo . Mol Cell Pediatr 2 (Suppl 1), A25 (2015). https://doi.org/10.1186/2194-7791-2-S1-A25
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DOI: https://doi.org/10.1186/2194-7791-2-S1-A25