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

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-1α, 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.

Pubmed ID: 21803289

Authors

  • Birkenfeld AL
  • Lee HY
  • Guebre-Egziabher F
  • Alves TC
  • Jurczak MJ
  • Jornayvaz FR
  • Zhang D
  • Hsiao JJ
  • Martin-Montalvo A
  • Fischer-Rosinsky A
  • Spranger J
  • Pfeiffer AF
  • Jordan J
  • Fromm MF
  • König J
  • Lieske S
  • Carmean CM
  • Frederick DW
  • Weismann D
  • Knauf F
  • Irusta PM
  • De Cabo R
  • Helfand SL
  • Samuel VT
  • Shulman GI

Journal

Cell metabolism

Publication Data

August 3, 2011

Associated Grants

  • Agency: NIDDK NIH HHS, Id: P30 DK-034989
  • Agency: NIDDK NIH HHS, Id: P30 DK-45735
  • Agency: NIA NIH HHS, Id: R01 AG023686
  • Agency: NIA NIH HHS, Id: R01 AG023686-08
  • Agency: NIA NIH HHS, Id: R01 AG024353
  • Agency: NIDDK NIH HHS, Id: R01 DK-40936
  • Agency: NIDDK NIH HHS, Id: R01 DK040936
  • Agency: NIDDK NIH HHS, Id: R01 DK040936-23
  • Agency: NIDDK NIH HHS, Id: R24 DK085638
  • Agency: NIA NIH HHS, Id: R37 AG-16667
  • Agency: NIA NIH HHS, Id: R37 AG016667
  • Agency: NIA NIH HHS, Id: R37 AG016667-14
  • Agency: NIDDK NIH HHS, Id: U24 DK-59635
  • Agency: NIDDK NIH HHS, Id: U24 DK059635
  • Agency: NIDDK NIH HHS, Id: U24 DK059635-06
  • Agency: Howard Hughes Medical Institute, Id:
  • Agency: Intramural NIH HHS, Id:

Mesh Terms

  • Adiposity
  • Aging
  • Animals
  • Caloric Restriction
  • Dicarboxylic Acid Transporters
  • Energy Metabolism
  • HEK293 Cells
  • Humans
  • Insulin Resistance
  • Lipid Metabolism
  • Mice
  • Mice, Knockout
  • Mitochondria
  • Obesity
  • Symporters