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Regulation of Energy Metabolism and Life Span in Mammals through Indy and its

Subject Area Endocrinology, Diabetology, Metabolism
Gastroenterology
Term from 2011 to 2019
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 204152872
 
Final Report Year 2020

Final Report Abstract

Before submitting the application, it was known that the reduced expression of the Indy gene in D. melanogaster prolongs lifespan. The underlying mechanism seemed to have similarities to caloric restriction. Within the scope of the application we could prove that the Indy homolog SLC13A5 (mindy) is involved in metabolic regulation in a mammalian model organism. Deletion of the gene in mice led to attenuated nutritionally induced obesity, insulin resistance, and fatty liver in mice. We could demonstrate that these effects were mediated at least in part by the interaction of mindy in the liver and nervous system, and that a temporal effect relationship exists. Whether other organs also contribute to this effect and which areas of the nervous system exactly mediate the effect must be clarified in follow-up studies. The question is of interest for a possible drug development. Mechanistically, we observed a depletion of biochemical energy in the form of ATP in the liver upon deletion of mINDY, with subsequent activation of AMPK, hepatic lipid oxidation and reduced hepatic lipogenesis. According to our data, an additional underlying mechanism may be the regulation of histone acetylation, a fundamental principle in protein function and gene expression. This new effect needs to be further investigated in future studies. Moreover, we were able to show that the proinflammatory cytokine IL-6 leads to an increased expression of mindy in the liver via the transcription actor STAT-3 in mice and humans, and that this mechanism explains an increased expression of mindy in obesity; insulin resistance and NAFLD. The increased expression of mindy in HepG2 and HEK cell lines resulted in an increased synthesis of triglyorides and sterols. This effect could be inhibited by reduced expression of mindy. In conclusion, we postulate that a dietary weight gain and insulin resistance, usually accompanied by elevated IL-6 concentrations, leads to increased expression of the citrate transporter mINDY. According to our data, reduced expression of the transporter would be a valid therapeutic principle in type 2 diabetes, insulin resistance and NAFLD. Based on our data, first mindy inhibitory compounds were developed by industry. https://www.taqesspieqel.de/themen/presseportal/taqesspiegel-magazine-taqesspiegel-gesund/13530724.html https://dresdner-transferbrief.de/ist-das-geheimnis-um-langlebigkeit-bald-gelueftet-und-fuer-den-menschen-nutzbar/ https://www.mdr.de/wissen/prof-andreas-birkenfeld-tu-dresden-100.html https://www.mdr.de/sachsenradio/bild-107636.html

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