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The longevity gene INDY (I'm Not Dead Yet) in metabolic control: Potential as pharmacological target

Willmes, Diana M. and Kurzbach, Anica and Henke, Christine and Schumann, Tina and Zahn, Gritt and Heifetz, Alexander and Jordan, Jens and Helfand, Stephen L. and Birkenfeld, Andreas L. (2018) The longevity gene INDY (I'm Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacology and Therapeutics (185), pp. 1-11. Elsevier. DOI: 10.1016/j.pharmthera.2017.10.003 ISSN 0163-7258

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Official URL: https://www.sciencedirect.com/science/article/pii/S0163725817302401

Abstract

The regulation of metabolic processes by the Indy (I′m Not Dead Yet) (SLC13A5/NaCT) gene was revealed through studies in Drosophila melanogaster and Caenorhabditis elegans. Reducing the expression of Indy in these species extended their life span by a mechanism resembling caloric restriction, without reducing food intake. In D. melanogaster, mutating the Indy gene reduced body fat content, insulin-like proteins and reactive oxygen species production. Subsequent studies indicated that Indy encodes a citrate transporter located on the cell plasma membrane. The transporter is highly expressed in the mammalian liver. We generated a mammalian knock out model deleting the mammalian homolog mIndy (SLC13A5). The knock out animals were protected from HFD induced obesity, fatty liver and insulin resistance. Moreover, we have shown that inducible and liver selective knock down of mIndy protects against the development of fatty liver and insulin resistance and that obese humans with type 2 diabetes and non-alcoholic fatty liver disease have increased levels of mIndy. Therefore, the transporter mINDY (NaCT) has been proposed to be an ‘ideal target for the treatment of metabolic disease’. A small molecule inhibitor of the mINDY transporter has been generated, normalizing glucose Levels and reducing fatty liver in a model of diet induced obese mice. Taken together, studies from lower organisms, mammals and humans suggest that mINDY (NaCT) is an attractive target for the treatment of metabolic disease.

Item URL in elib:https://elib.dlr.de/124632/
Document Type:Article
Title:The longevity gene INDY (I'm Not Dead Yet) in metabolic control: Potential as pharmacological target
Authors:
AuthorsInstitution or Email of AuthorsAuthors ORCID iD
Willmes, Diana M.University Hospital Dresden, Dresden, GermanyUNSPECIFIED
Kurzbach, AnicaUniversity School of Medicine, Technische Universität DresdenUNSPECIFIED
Henke, ChristineDresden University School of Medicine, Technische Universität DresdenUNSPECIFIED
Schumann, TinaDresden University School of Medicine, Technische Universität DresdenUNSPECIFIED
Zahn, GrittEternygen GmbH, Berlin, GermanyUNSPECIFIED
Heifetz, AlexanderEvotec UK Ltd., Abingdon, UKUNSPECIFIED
Jordan, Jensgerman aerospace centre (dlr), institute of aerospace medicine, gravitational biology, cologne, germanyUNSPECIFIED
Helfand, Stephen L.Brown University, Providence, RIUNSPECIFIED
Birkenfeld, Andreas L.University Hospital Dresden, Dresden, GermanyUNSPECIFIED
Date:May 2018
Journal or Publication Title:Pharmacology and Therapeutics
Refereed publication:Yes
Open Access:Yes
Gold Open Access:No
In SCOPUS:Yes
In ISI Web of Science:Yes
DOI :10.1016/j.pharmthera.2017.10.003
Page Range:pp. 1-11
Publisher:Elsevier
ISSN:0163-7258
Status:Published
Keywords:INDY; metabolic disease; metabolism; insulin resistance; mice; fatty liver;
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Forschung unter Weltraumbedingungen
DLR - Research theme (Project):R - Vorhaben Systemphysiologie
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Muscle and Bone Metabolism
Deposited By: Becker, Christine
Deposited On:11 Dec 2018 12:06
Last Modified:20 Jan 2020 13:25

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