title: TFE3 regulates whole-body energy metabolism in cooperation with TFEB.
abstract: TFE3 and TFEB are members of the MiT family of HLH-leucine zipper transcription factors. Recent studies demonstrated that they bind overlapping sets of promoters and are post-transcriptionally regulated through a similar mechanism. However, whileTcfebknockout (KO) mice die during early embryonic development, no apparent phenotype was reported inTfe3KO mice. Thus raising the need to characterize the physiological role of TFE3 and elucidate its relationship with TFEB TFE3 deficiency resulted in altered mitochondrial morphology and function bothin vitroandin vivodue to compromised mitochondrial dynamics. In addition,Tfe3KO mice showed significant abnormalities in energy balance and alterations in systemic glucose and lipid metabolism, resulting in enhanced diet-induced obesity and diabetes. Conversely, viral-mediated TFE3 overexpression improved the metabolic abnormalities induced by high-fat diet (HFD). Both TFEB overexpression inTfe3KO mice and TFE3 overexpression inTcfebliver-specific KO mice (TcfebLiKO) rescued HFD-induced obesity, indicating that TFEB can compensate for TFE3 deficiency andvice versaAnalysis ofTcfebLiKO/Tfe3double KO mice demonstrated that depletion of both TFE3 and TFEB results in additive effects with an exacerbation of the hepatic phenotype. These data indicate that TFE3 and TFEB play a cooperative, rather than redundant, role in the control of the adaptive response of whole-body metabolism to environmental cues such as diet and physical exercise.
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Nunzia
authors.initials: N
authors.lastname: Pastore
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Vainshtein
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Tiemo J
authors.initials: TJ
authors.lastname: Klisch
authors.affiliation: Department of Biomedical Science, University of Padova, Padova, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Armani
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Tuong
authors.initials: T
authors.lastname: Huynh
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Niculin J
authors.initials: NJ
authors.lastname: Herz
authors.affiliation: Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy.
authors.forename: Elena V
authors.initials: EV
authors.lastname: Polishchuk
authors.affiliation: Department of Biomedical Science, University of Padova, Padova, Italy.|Venetian Institute of Molecular Medicine, Padova, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Sandri
authors.affiliation: Jan and Dan Duncan Neurological Research Institute, Texas Children Hospital, Houston, TX, USA ballabio@tigem.it.|Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.|Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli (Naples), Italy.|Medical Genetics, Department of Medical and Translational Sciences, Federico II University, Naples, Italy.
authors.forename: Andrea
authors.identifier: 0000-0003-1381-4604
authors.initials: A
authors.lastname: Ballabio
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004734:Energy Metabolism; D005947:Glucose / Q000378:metabolism; D050356:Lipid Metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063154:Mitochondrial Dynamics; D010805:Physical Conditioning, Animal; D015854:Up-Regulation
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C484068:Tcfeb protein, mouse; C068486:Tcfe3 protein, mouse; D005947:Glucose
keywords: 
  TFEB
  ; TFE3; lipid metabolism; mitochondrial dynamics; physical exercise