title: 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-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.
authors.affiliation: Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Andreas L
authors.initials: AL
authors.lastname: Birkenfeld
authors.forename: Hui-Young
authors.initials: HY
authors.lastname: Lee
authors.forename: Fitsum
authors.initials: F
authors.lastname: Guebre-Egziabher
authors.forename: Tiago C
authors.initials: TC
authors.lastname: Alves
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Jurczak
authors.forename: Francois R
authors.initials: FR
authors.lastname: Jornayvaz
authors.forename: Dongyang
authors.initials: D
authors.lastname: Zhang
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Hsiao
authors.forename: Alejandro
authors.initials: A
authors.lastname: Martin-Montalvo
authors.forename: Antje
authors.initials: A
authors.lastname: Fischer-Rosinsky
authors.forename: Joachim
authors.initials: J
authors.lastname: Spranger
authors.forename: Andreas F
authors.initials: AF
authors.lastname: Pfeiffer
authors.forename: Jens
authors.initials: J
authors.lastname: Jordan
authors.forename: Martin F
authors.initials: MF
authors.lastname: Fromm
authors.forename: Jörg
authors.initials: J
authors.lastname: König
authors.forename: Stefanie
authors.initials: S
authors.lastname: Lieske
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Carmean
authors.forename: David W
authors.initials: DW
authors.lastname: Frederick
authors.forename: Dirk
authors.initials: D
authors.lastname: Weismann
authors.forename: Felix
authors.initials: F
authors.lastname: Knauf
authors.forename: Pablo M
authors.initials: PM
authors.lastname: Irusta
authors.forename: Rafael
authors.initials: R
authors.lastname: De Cabo
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Helfand
authors.forename: Varman T
authors.initials: VT
authors.lastname: Samuel
authors.forename: Gerald I
authors.initials: GI
authors.lastname: Shulman
mesh_terms: D050154:Adiposity / Q000235:genetics*; D000375:Aging; D000818:Animals; D031204:Caloric Restriction; D029382:Dicarboxylic Acid Transporters; D004734:Energy Metabolism / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D050356:Lipid Metabolism / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D009765:Obesity / Q000235:genetics; D027981:Symporters / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics
chemical_list: D029382:Dicarboxylic Acid Transporters; C487219:Slc13a5 protein, mouse; D027981:Symporters