Universität zu Köln

Willmes, Diana M., Kurzbach, Anica, Henke, Christine, Schumann, Tina, Zahn, Grit, Heifetz, Alexander, Jordan, Jens, Helfand, Stephen L. and Birkenfeld, Andreas L. ORCID: 0000-0003-1407-9023 (2018). The longevity gene INDY (I'm Not Dead Yet) in metabolic control: Potential as pharmacological target. Pharmacol. Ther., 185. S. 1 - 12. OXFORD: PERGAMON-ELSEVIER SCIENCE LTD. ISSN 0163-7258

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Abstract

The regulation of metabolic processes by the Indy (Fin 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 Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Willmes, Diana M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kurzbach, Anica UNSPECIFIED UNSPECIFIED UNSPECIFIED Henke, Christine UNSPECIFIED UNSPECIFIED UNSPECIFIED Schumann, Tina UNSPECIFIED UNSPECIFIED UNSPECIFIED Zahn, Grit UNSPECIFIED UNSPECIFIED UNSPECIFIED Heifetz, Alexander UNSPECIFIED UNSPECIFIED UNSPECIFIED Jordan, Jens UNSPECIFIED UNSPECIFIED UNSPECIFIED Helfand, Stephen L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Birkenfeld, Andreas L. UNSPECIFIED orcid.org/0000-0003-1407-9023 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-187446
DOI:	10.1016/j.pharmthera.2017.10.003
Journal or Publication Title:	Pharmacol. Ther.
Volume:	185
Page Range:	S. 1 - 12
Date:	2018
Publisher:	PERGAMON-ELSEVIER SCIENCE LTD
Place of Publication:	OXFORD
ISSN:	0163-7258
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FATTY LIVER-DISEASE; COUPLED CITRATE TRANSPORTER; HEPATIC INSULIN-RESISTANCE; DEPENDENT DICARBOXYLATE TRANSPORTER; NEURONAL PYRUVATE CARBOXYLATION; FUNCTIONAL-CHARACTERIZATION; SLC13 FAMILY; LIFE-SPAN; GENOMIC ORGANIZATION; NA+/DICARBOXYLATE COTRANSPORTER Multiple languages Pharmacology & Pharmacy Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/18744