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

• Published in: Cell metabolism Vol. 14; no. 2; pp. 184 - 195
• Main Authors: Birkenfeld, Andreas L., Lee, Hui-Young, Guebre-Egziabher, Fitsum, Alves, Tiago C., Jurczak, Michael J., Jornayvaz, Francois R., Zhang, Dongyang, Hsiao, Jennifer J., Martin-Montalvo, Alejandro, Fischer-Rosinsky, Antje, Spranger, Joachim, Pfeiffer, Andreas F., Jordan, Jens, Fromm, Martin F., König, Jörg, Lieske, Stefanie, Carmean, Christopher M., Frederick, David W., Weismann, Dirk, Knauf, Felix, Irusta, Pablo M., De Cabo, Rafael, Helfand, Stephen L., Samuel, Varman T., Shulman, Gerald I.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.08.2011
• Subjects: Adiposity - genetics; Aging; Animals; Caloric Restriction; Dicarboxylic Acid Transporters; Energy Metabolism - genetics; HEK293 Cells; Humans; Insulin Resistance - genetics; Lipid Metabolism - genetics; Mice; Mice, Knockout; Mitochondria - genetics; Mitochondria - metabolism; Obesity - genetics; Symporters - biosynthesis; Symporters - deficiency; Symporters - genetics
• ISSN: 1550-4131; 1932-7420
• DOI: 10.1016/j.cmet.2011.06.009

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. [Display omitted] ► A mIndy ( SLC13A5) knockout mouse was generated ► Loss of mIndy decreases hepatic ATP/ADP ratio and activates AMPK ► mIndy deletion promotes mitochondrial biogenesis and energy expenditure ► Loss of mIndy protects from diet- and age-associated insulin resistance