title: THADA Regulates the Organismal Balance between Energy Storage and Heat Production.
abstract: Human susceptibility to obesity is mainly genetic, yet the underlying evolutionary drivers causing variation from person to person are not clear. One theory rationalizes that populations that have adapted to warmer climates have reduced their metabolic rates, thereby increasing their propensity to store energy. We uncover here the function of a gene that supports this theory. THADA is one of the genes most strongly selected during evolution as humans settled in different climates. We report here that THADA knockout flies are obese, hyperphagic, have reduced energy production, and are sensitive to the cold. THADA binds the sarco/ER Ca2+ATPase (SERCA) and acts on it as an uncoupler. Reducing SERCA activity in THADA mutant flies rescues their obesity, pinpointing SERCA as a key effector of THADA function. In sum, this identifies THADA as a regulator of the balance between energy consumption and energy storage, which was selected during human evolution.
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Moraru
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Gulcin
authors.initials: G
authors.lastname: Cakan-Akdogan
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Strassburger
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Matilda
authors.initials: M
authors.lastname: Males
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Sandra
authors.initials: S
authors.lastname: Mueller
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Jabs
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Muelleder
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Frejno
authors.affiliation: Department of Biology, Ghent University, 9000 Ghent, Belgium.
authors.forename: Bart P
authors.initials: BP
authors.lastname: Braeckman
authors.affiliation: Department of Biochemistry and Cambridge Systems Biology Centre, University of Cambridge, 80 Tennis Court Road, Cambridge CB2 1GA, UK; Molecular Biology of Metabolism Laboratory, The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
authors.forename: Markus
authors.initials: M
authors.lastname: Ralser
authors.affiliation: German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany. Electronic address: a.teleman@dkfz.de.
authors.forename: Aurelio A
authors.initials: AA
authors.lastname: Teleman
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D017124:Conserved Sequence; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D055786:Gene Knockout Techniques; D006367:HeLa Cells; D006358:Hot Temperature; D006801:Humans; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000378:metabolism*; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D011485:Protein Binding; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D029721:Drosophila Proteins; D009363:Neoplasm Proteins; C000620812:THADA protein, Drosophila; C477698:THADA protein, human; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
keywords: Drosophila; SERCA; calcium; development; metabolism; obesity; sarcolipin; thermogenesis; type 2 diabetes