title: 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.
authors.affiliation: PhD, or Hitoshi Shimano, MD, PhD, Department of Internal Medicine (Metabolism and Endocrinology), Faculty of Medicine, University of Tsukuba, 1-1-1, Tennodai, Tsukuba, Japan 305-8575. hshimano@md.tsukuba.ac.jp; or ynakagawa@md.tsukuba.ac.jp.
authors.forename: Yuri
authors.initials: Y
authors.lastname: Fujimoto
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Nakagawa
authors.forename: Aoi
authors.initials: A
authors.lastname: Satoh
authors.forename: Kanako
authors.initials: K
authors.lastname: Okuda
authors.forename: Akiko
authors.initials: A
authors.lastname: Shingyouchi
authors.forename: Ayano
authors.initials: A
authors.lastname: Naka
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsuzaka
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Iwasaki
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Naoya
authors.initials: N
authors.lastname: Yahagi
authors.forename: Masako
authors.initials: M
authors.lastname: Shimada
authors.forename: Shigeru
authors.initials: S
authors.lastname: Yatoh
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suzuki
authors.forename: Satomi
authors.initials: S
authors.lastname: Yogosawa
authors.forename: Tetsuro
authors.initials: T
authors.lastname: Izumi
authors.forename: Hirohito
authors.initials: H
authors.lastname: Sone
authors.forename: Osamu
authors.initials: O
authors.lastname: Urayama
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Yamada
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Shimano
mesh_terms: D041721:3T3-L1 Cells; D050156:Adipogenesis; D002001:Adipose Tissue, Brown / Q000378:metabolism* / Q000473:pathology; D052436:Adipose Tissue, White / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D015536:Down-Regulation; D050556:Fatty Acid-Binding Proteins / Q000235:genetics / Q000378:metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D008049:Lipase / Q000235:genetics / Q000378:metabolism; D008066:Lipolysis; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D000070778:Perilipin-1; D010750:Phosphoproteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000378:metabolism; D022722:Thermogenesis; D000071256:Uncoupling Protein 1; D000217:Acyltransferases
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050556:Fatty Acid-Binding Proteins; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D007473:Ion Channels; D008049:Lipase; D024101:Mitochondrial Proteins; D000070778:Perilipin-1; D010750:Phosphoproteins; D011994:Recombinant Proteins; D000071256:Uncoupling Protein 1; C493411:Fabp4 protein, mouse; C467200:Foxo1 protein, mouse; C508072:G0S2 protein, mouse; C000604372:Ucp1 protein, mouse; C068486:Tcfe3 protein, mouse; C494445:PNPLA2 protein, mouse; D000217:Acyltransferases