Coordinated transcriptional control of adipocyte triglyceride lipase (Atgl) by transcription factors Sp1 and peroxisome proliferator–activated receptor γ (PPARγ) during adipocyte differentiation

Abstract

The breakdown of stored fat deposits into its components is a highly regulated process that maintains plasma levels of free fatty acids to supply energy to cells. Insulin-mediated transcription of <i>Atgl</i>, the enzyme that mediates the rate-limiting step in lipolysis, is a key point of this regulation. Under conditions such as obesity or insulin resistance, <i>Atgl</i> transcription is often misregulated, which can contribute to overall disease progression. The mechanisms by which <i>Atgl</i> is induced during adipogenesis are not fully understood. We utilized computational approaches to identify putative transcriptional regulatory elements in <i>Atgl</i> and then tested the effect of these elements and the transcription factors that bind to them in cultured preadipocytes and mature adipocytes. Here we report that <i>Atgl</i> is down-regulated by the basal transcription factor Sp1 in preadipocytes and that the magnitude of down-regulation depends on interactions between Sp1 and peroxisome proliferator-activated receptor γ (PPARγ). In mature adipocytes, when PPARγ is abundant, PPARγ abrogated transcriptional repression by Sp1 at the <i>Atgl</i> promoter and up-regulated <i>Atgl</i> mRNA expression. Targeting the PPARγ-Sp1 interaction could be a potential therapeutic strategy to restore insulin sensitivity by modulating <i>Atgl</i> levels in adipocytes.