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Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice.

ABSTRACT: Reduced expression of the Indy (I'm Not Dead, Yet) gene in D. melanogaster and its homolog in C. elegans prolongs life span and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which Indy does this is unknown. Here, we report on the knockout mouse model of the mammalian Indy (mIndy) homolog, SLC13A5. Deletion of mIndy in mice (mINDY(-/-) mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC-1?, inhibits ACC-2, and reduces SREBP-1c levels. This signaling network promotes hepatic mitochondrial biogenesis, lipid oxidation, and energy expenditure and attenuates hepatic de novo lipogenesis. Together, these traits protect mINDY(-/-) mice from the adiposity and insulin resistance that evolve with high-fat feeding and aging. Our studies demonstrate a profound effect of mIndy on mammalian energy metabolism and suggest that mINDY might be a therapeutic target for the treatment of obesity and type 2 diabetes.

SUBMITTER: Birkenfeld AL

PROVIDER: S-EPMC3163140 | biostudies-literature | 2011 Aug

REPOSITORIES: biostudies-literature

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Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice.

Birkenfeld Andreas L AL Lee Hui-Young HY Guebre-Egziabher Fitsum F Alves Tiago C TC Jurczak Michael J MJ Jornayvaz Francois R FR Zhang Dongyang D Hsiao Jennifer J JJ Martin-Montalvo Alejandro A Fischer-Rosinsky Antje A Spranger Joachim J Pfeiffer Andreas F AF Jordan Jens J Fromm Martin F MF König Jörg J Lieske Stefanie S Carmean Christopher M CM Frederick David W DW Weismann Dirk D Knauf Felix F Irusta Pablo M PM De Cabo Rafael R De Cabo Rafael R Helfand Stephen L SL Samuel Varman T VT Shulman Gerald I GI

Cell metabolism 20110801 2

Reduced expression of the Indy (I'm Not Dead, Yet) gene in D. melanogaster and its homolog in C. elegans prolongs life span and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which Indy does this is unknown. Here, we report on the knockout mouse model of the mammalian Indy (mIndy) homolog, SLC13A5. Deletion of mIndy in mice (mINDY(-/-) mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC- ...[more]

PMID: 21803289

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Project description:Reduction in expression of the INDY gene in Drosophila melanogaster and Caenorhabditis elegans prolongs life span, and in D. melanogaster augments mitochondrial biogenesis in a manner akin to caloric restriction. However, the cellular mechanism by which INDY does this is unknown. In order to examine the effect that INDY might have on energy metabolism and insulin sensitivity in mammals we created the first knock out mouse model of the mammalian INDY homologue SLC13A5. Here, we show that deletion of the mammalian homologue of INDY, SLC13A5 (mINDY) in mice (mINDY-/- mice) have increased mitochondrial biogenesis, hepatic lipid oxidation, and energy expenditure, but decreased hepatic de novo lipogenesis. Loss of mIndy activates hepatic AMPK, which induces PGC-1?, inhibits ACC-2, and reduces SREBP-1c levels. In contrast to wild- type mice, mINDY-/- mice have reduced body weight and are protected from insulin resistance that evolves with high-fat feeding and aging. These studies demonstrate that mIndy functions as a novel regulator of mammalian energy metabolism and suggest that mIndy might be a novel therapeutic target for the treatment of obesity and type 2 diabetes. An SLC13A5 knockout mouse model (mINDY-/-) was generated. The litters produced when heterozygous (KO/+) mINDY mice (mINDY+/-) were bred, contained the expected ratio of Illumina Mouse-ref8Indy wild-type (mINDY+/+), mINDY+/- mice, and homozygous mIndy (mINDY-/-) pups, indicating no substantial embryonic lethality. In wild-type mice, Indy mRNA expression was highest in liver, and very low in white adipose tissue, brown adipose tissue, skeletal muscle, small and large intestines and the pancreas confirming previous mINDY expression levels in rodents, and humans. In the liver, mINDY mRNA expression was completely abolished in the INDY-/- mice and ~50% reduced in heterozygous mINDY+/- mice. Total RNA from the Liver tissue of 5 replicate Wt and 5 replicate Knockout mice were labeled and hybridized to Illumina Mouse-ref8 v2 bead arrays. Analysis of gene expression was carried out by Hierarchy clustering/K-means clustering and Principal Components Analysis (PCA), as well as The Parameterized Analysis of Gene Enrichment (PAGE) and Ingenuity Pathways Analysis IPA (Ingenuity Systems, CA, USA).

Project description:Reduced expression of the Indy ("I am Not Dead, Yet") gene in lower organisms promotes longevity in a manner akin to caloric restriction. Deletion of the mammalian homolog of Indy (mIndy, Slc13a5) encoding for a plasma membrane-associated citrate transporter expressed highly in the liver, protects mice from high-fat diet-induced and aging-induced obesity and hepatic fat accumulation through a mechanism resembling caloric restriction. We studied a possible role of mIndy in human hepatic fat metabolism. In obese, insulin-resistant patients with nonalcoholic fatty liver disease, hepatic mIndy expression was increased and mIndy expression was also independently associated with hepatic steatosis. In nonhuman primates, a 2-year high-fat, high-sucrose diet increased hepatic mIndy expression. Liver microarray analysis showed that high mIndy expression was associated with pathways involved in hepatic lipid metabolism and immunological processes. Interleukin-6 (IL-6) was identified as a regulator of mIndy by binding to its cognate receptor. Studies in human primary hepatocytes confirmed that IL-6 markedly induced mIndy transcription through the IL-6 receptor and activation of the transcription factor signal transducer and activator of transcription 3, and a putative start site of the human mIndy promoter was determined. Activation of the IL-6-signal transducer and activator of transcription 3 pathway stimulated mIndy expression, enhanced cytoplasmic citrate influx, and augmented hepatic lipogenesis in vivo. In contrast, deletion of mIndy completely prevented the stimulating effect of IL-6 on citrate uptake and reduced hepatic lipogenesis. These data show that mIndy is increased in liver of obese humans and nonhuman primates with NALFD. Moreover, our data identify mIndy as a target gene of IL-6 and determine novel functions of IL-6 through mINDY. CONCLUSION:Targeting human mINDY may have therapeutic potential in obese patients with nonalcoholic fatty liver disease. German Clinical Trials Register: DRKS00005450. (Hepatology 2017;66:616-630).

Dataset Information

Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice.

Publications

Deletion of the mammalian INDY homolog mimics aspects of dietary restriction and protects against adiposity and insulin resistance in mice.

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