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Willmes, D.M. ; Kurzbach, A. ; Henke, C. ; Zahn, G.* ; Heifetz, A.* ; Jordan, J.* ; Helfand, S.L.* ; Birkenfeld, A.L.

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

Pharmacol. Ther., DOI: 10.1016/j.pharmthera.2017.10.003 (2017)
Postprint DOI PMC
Open Access Green
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.
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Publication type Article: Journal article
Document type Scientific Article
Language english
Publication Year 2017
HGF-reported in Year 2017
ISSN (print) / ISBN 0163-7258
e-ISSN 1879-016X
Journal Pharmacology & Therapeutics.
Publisher Elsevier
Reviewing status Peer reviewed
Institute(s) Institute of Pancreatic Islet Research (IPI)
POF-Topic(s) 90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
PSP Element(s) G-502600-012
DOI 10.1016/j.pharmthera.2017.10.003
PubMed ID 28987323
Erfassungsdatum 2017-10-17
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