Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Deletion of the Mammalian INDY Homologue in Mice Mimics Aspects of Dietary Restriction and Protects Against Diet and Age-Induced Adiposity and Insulin Resistance

ABSTRACT: 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).

ORGANISM(S): Mus musculus

SUBMITTER: Kevin Becker

PROVIDER: E-GEOD-29984 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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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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Dataset Information

Deletion of the Mammalian INDY Homologue in Mice Mimics Aspects of Dietary Restriction and Protects Against Diet and Age-Induced Adiposity and Insulin Resistance

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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