Abstract
TMEM18 is the strongest risk factor for childhood obesity identified from GWAS. We here investigated the functional relevance of TMEM18 for adipose tissue development and obesity. We demonstrate that adipocyte TMEM18 expression is down-regulated in obese children. Functionally, such a down-regulation of TMEM18 impairs adipocyte formation in zebrafish and in human preadipocytes indicating that TMEM18 is important for adipose-derived stem cell differentiation in vivo and in vitro. On the molecular level, TMEM18 activates PPARG through direct interaction with the PPARG promoter and this activation is repressed by inflammatory stimuli in human and mouse adipocyte models. The relationship between TMEM18 and PPARG is also evident in adipocytes of children and is clinically associated with obesity and related adipocyte hypertrophy, inflammation and insulin resistance. Our findings indicate a role of TMEM18 as a direct activator of PPARG signaling driving healthy adipogenesis which is dysregulated with adipose tissue dysfunction and obesity.
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