Deletion of the Mammalian INDY Homo log Mimics Aspects of Dietary Restriction and Protects against Adiposity and Insulin Resistance in Mice

被引：168

作者：

Birkenfeld, Andreas L. ^{[1
,2
,3
,4
,5
]}

Lee, Hui-Young ^{[1
,2
,3
]}

Guebre-Egziabher, Fitsum ^{[1
,2
,3
]}

Alves, Tiago C. ^{[1
,2
,3
]}

Jurczak, Michael J. ^{[1
,2
,3
]}

Jornayvaz, Francois R. ^{[1
,2
,3
]}

Zhang, Dongyang ^{[1
,2
,3
]}

Hsiao, Jennifer J. ^{[1
,2
,3
]}

Martin-Montalvo, Alejandro ^{[6
]}

Fischer-Rosinsky, Antje ^{[5
]}

Spranger, Joachim ^{[4
,5
]}

Pfeiffer, Andreas F. ^{[4
,5
]}

Jordan, Jens ^{[7
]}

Fromm, Martin F. ^{[8
]}

Koenig, Joerg ^{[8
]}

Lieske, Stefanie ^{[4
]}

Carmean, Christopher M. ^{[1
,2
,3
]}

Frederick, David W. ^{[1
,2
,3
]}

Weismann, Dirk ^{[1
,2
,3
]}

Knauf, Felix ^{[1
,2
,3
]}

Irusta, Pablo M. ^{[9
]}

De Cabo, Rafael ^{[6
]}

Helfand, Stephen L. ^{[10
]}

Samuel, Varman T. ^{[1
,2
,3
]}

Shulman, Gerald I. ^{[1
,2
,3
]}

机构：

[1] Yale Univ, Sch Med, Howard Hughes Med Inst, New Haven, CT 06520 USA

[2] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA

[3] Yale Univ, Sch Med, Dept Cellular & Mol Physiol, New Haven, CT 06520 USA

[4] German Inst Human Nutr Potsdam Rehbrucke, D-14558 Nuthetal, Germany

[5] Charite Univ Sch Med, D-10117 Berlin, Germany

[6] NIA, Lab Expt Gerontol, Baltimore, MD 21224 USA

[7] Hannover Med Sch, Inst Clin Pharmacol, D-30625 Hannover, Germany

[8] Univ Erlangen Nurnberg, Inst Expt & Clin Pharmacol & Toxicol, D-91023 Erlangen, Germany

[9] Georgetown Univ, Dept Human Sci, Washington, DC 20057 USA

[10] Brown Univ, Dept Mol Biol Cell Biol & Biochem, Providence, RI 02912 USA

来源：

CELL METABOLISM | 2011年 / 14卷 / 02期

关键词：

COUPLED CITRATE TRANSPORTER; EXTENDING GENE INDY; FATTY LIVER-DISEASE; LIFE-SPAN; CALORIE RESTRICTION; MITOCHONDRIAL BIOGENESIS; CAENORHABDITIS-ELEGANS; INDUCED OBESITY; GLUCOSE-HOMEOSTASIS; CHRONIC ACTIVATION;

D O I：

10.1016/j.cmet.2011.06.009

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 mlndy in mice (mINDY(-/-) mice) reduces hepatocellular ATP/ADP ratio, activates hepatic AMPK, induces PGC-1 alpha, 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 mlndy on mammalian energy metabolism and suggest that mINDY might be a therapeutic target for the treatment of obesity and type 2 diabetes.

引用

页码：184 / 195

页数：12

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