TFE3 Controls Lipid Metabolism in Adipose Tissue of Male Mice by Suppressing Lipolysis and Thermogenesis

Abstract

Transcription factor E3 (TFE3) is a transcription factor that binds to E-box motifs and promotes energy metabolism-related genes. We previously reported that TFE3 directly binds to the insulin receptor substrate-2 promoter in the liver, resulting in increased insulin response. However, the role of TFE3 in other tissues remains unclear. In this study, we generated adipose-specific TFE3 transgenic (aP2-TFE3 Tg) mice. These mice had a higher weight of white adipose tissue (WAT) and brown adipose tissue than wild-type (WT) mice under fasting conditions. Lipase activity in the WAT in these mice was lower than that in the WT mice. The mRNA level of adipose triglyceride lipase (ATGL), the rate-limiting enzyme for adipocyte lipolysis, was significantly decreased in aP2-TFE3 Tg mice. The expression of Foxo1, which directly activates ATGL expression, was also suppressed in transgenic mice. Promoter analysis confirmed that TFE3 suppressed promoter activities of the ATGL gene. In contrast, G0S2 and Perilipin1, which attenuate ATGL activity, were higher in transgenic mice than in WT mice. These results indicated that the decrease in lipase activity in adipose tissues was due to a decrease in ATGL expression and suppression of ATGL activity. We also showed that thermogenesis was suppressed in aP2-TFE3 Tg mice. The decrease in lipolysis in WAT of aP2-TFE3 Tg mice inhibited the supply of fatty acids to brown adipose tissue, resulting in the inhibition of the expression of thermogenesis-related genes such as UCP1. Our data provide new evidence that TFE3 regulates lipid metabolism by controlling the gene expression related to lipolysis and thermogenesis in adipose tissue.

Tfe3 and Tfeb Transcriptionally Regulate Peroxisome Proliferator-Activated Receptor γ2 Expression in Adipocytes and Mediate Adiponectin and Glucose Levels in Mice

“…Given prior evidence that Tfe3 participates in metabolic regulation of various tissues (9,15,16,18) and the structural/functional overlap among members of the MiT transcription factor family (4,14,33), we decided to investigate their expression levels in several organs after a 16-h fasting and 12-h refeeding of C57BL/6J (B6) mice. As shown in Fig.…”

“…Recently it was shown that Tfe3 and Tfeb transactivate E-box-containing promoters of genes implicated in metabolism (9,10,(15)(16)(17)(18). These findings indicate that while there may be common targets for certain MiT members, the individual factors may also regulate unique target genes or exhibit distinct expression patterns which result in lineage-specific gene expression.…”

“…These transcription factors homodimerize or heterodimerize in all combinations and bind to E-box motifs (2)(3)(4)(5), suggesting that they may regulate common targets. The members of this family are implicated in essential developmental and cellular processes in a number of cell types, including melanocytes, bone marrow-derived mast cells, osteoclasts, T and B cells, macrophages, myotubes, and adipocytes (4)(5)(6)(7)(8)(9)(10). During development, Tfeb is implicated in the vascularization of placenta and Tfe3 in the exit from pluripotency (11,12).…”

“…Ectopic expression of Tfe3 in mouse liver and muscle results in upregulation of genes involved in insulin signaling and glucose metabolism, while overexpression in adipose tissue causes a decrease in expression of genes implicated in lipid metabolism (9,15). Because white adipose tissue (WAT) plays a major role in the control of whole-body metabolism, we investigated the role of MiT transcription factors (Tfeb and Tfe3) in the regulation of this tissue.…”

Improved methodologies for the study of adipose biology: insights gained and opportunities ahead

“…Importantly, many of the factors that regulate lipolysis are also regulated at the level of gene expression. This includes hormonesensitive lipase (HSL) itself, as well as transcription factors that control the expression of the lipolytic gene program (e.g., Tblr1 , Tfe3 , and Irf4 ) (21)(22)(23). Upon cold exposure, brown and beige adipocytes respond to adrenergic signals to induce thermogenic regulatory pathways.…”