SummaryCaloric restriction (CR) can delay onset of several age‐related pathophysiologies and extend lifespan in various species, including rodents. CR also induces metabolic remodeling involved in activation of lipid metabolism, enhancement of mitochondrial biogenesis, and reduction of oxidative stress in white adipose tissue (WAT). In studies using genetically modified mice with extended lifespans, WAT characteristics influenced mammalian lifespans. However, molecular mechanisms underlying CR‐associated metabolic remodeling of WAT remain unclear. Sterol regulatory element‐binding protein‐1c (Srebp‐1c), a master transcription factor of fatty acid (FA) biosynthesis, is responsible for the pathogenesis of fatty liver (steatosis). Our study showed that, under CR conditions, Srebp‐1c enhanced mitochondrial biogenesis via increased expression of peroxisome proliferator‐activated receptor gamma coactivator‐1α (Pgc‐1α) and upregulated expression of proteins involved in FA biosynthesis within WAT. However, via Srebp‐1c, most of these CR‐associated metabolic alterations were not observed in other tissues, including the liver. Moreover, our data indicated that Srebp‐1c may be an important factor both for CR‐associated suppression of oxidative stress, through increased synthesis of glutathione in WAT, and for the prolongevity action of CR. Our results strongly suggested that Srebp‐1c, the primary FA biosynthesis‐promoting transcriptional factor implicated in fatty liver disease, is also the food shortage‐responsive factor in WAT. This indicated that Srebp‐1c is a key regulator of metabolic remodeling leading to the beneficial effects of CR.

The role of the growth hormone (GH)-insulin-like growth factor (IGF)-1 axis in the lifelong caloric restriction (CR)-associated remodeling of white adipose tissue (WAT), adipocyte size, and gene expression profiles was explored in this study. We analyzed the WAT morphology of 6-7-month-old wild-type Wistar rats fed ad libitum (WdAL) or subjected to CR (WdCR), and of heterozygous transgenic dwarf rats bearing an anti-sense GH transgene fed ad libitum (TgAL) or subjected to CR (TgCR). Although less effective in TgAL, the adipocyte size was significantly reduced in WdCR compared with WdAL. This CR effect was blunted in Tg rats. We also used high-density oligonucleotide microarrays to examine the gene expression profile of WAT of WdAL, WdCR, and TgAL rats. The gene expression profile of WdCR, but not TgAL, differed greatly from that of WdAL. The gene clusters with the largest changes induced by CR but not by Tg were genes involved in lipid biosynthesis and inflammation, particularly sterol regulatory element binding proteins (SREBPs)-regulated and macrophage-related genes, respectively. Real-time reverse-transcription polymerase chain reaction analysis confirmed that the expression of SREBP-1 and its downstream targets was upregulated, whereas the macrophage-related genes were downregulated in WdCR, but not in TgAL. In addition, CR affected the gene expression profile of Tg rats similarly to wild-type rats. Our findings suggest that CR-associated remodeling of WAT, which involves SREBP-1-mediated transcriptional activation and suppression of macrophage infiltration, is regulated in a GH-IGF-1-independent manner. AGE (2013) 35:1143-1156 DOI 10.1007 Yoshikazu Chujo, Namiki Fujii, Naoyuki Okita, and Tomokazu Konishi contributed equally to this work. Electronic supplementary materialThe online version of this article