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

作者：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; Koenig Joerg; 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^*

来源：Cell Metabolism, 2011, 14(2): 184-195.

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 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.

• 出版日期2011-8-3