A novel caloric restriction mediator

Caloric restriction(definition) (CR) extends lifespan and suppresses age-associated pathophysiology in various animal models [1].However, the exact mechanisms underpinning these effects are still debated.White adipose tissue (WAT) is the main tissue for energy storage in the form of triglycerides.Moreover, it is accepted that WAT contributes to systemic metabolic dysfunctions including insulin resistance and cardioand cerebro-vascular diseases.Thus, the characteristics of WAT appear to influence age-associated pathophysiology and lifespan [2].In fact, it has been reported that various WAT-specific genetically modified models exhibit alterations in lifespan (references are presented in [3] and [4]).CR animals share many characteristics with long living dwarf mice with suppression of growth hormone/insulin-like growth factor (GH/IGF-1) signaling.However, CR further extends the lifespan of these mice, suggesting that the beneficial effects of CR are not only dependent on GH/IGF-1 signaling.Therefore, to identify genes altered by CR in GH/IGF-1-dependent or -independent manners, we previously compared gene expression profiles of WAT between CR rats and transgenic dwarf rats, bearing an antisense GH transgene.This analysis showed that CR induced expression of sterol regulatory element binding protein-1c (Srebp-1c) in a GH/IGF-1-independent manner [3].Srebp-1c is one of the SREBP isoforms, master transcriptional regulators of lipid metabolism.In agreement with this function, CR also upregulated the expression of genes involved in fatty acid (FA) biosynthesis in a GH/IGF-1-independent manner [3].In this previous study, we proposed that Srebp-1c-induced activation of FA biosynthesis is one of the major mechanisms by which CR changes metabolism in WAT [3].Thus, we concluded that activation of de novo FA biosynthesis via Srebp-1c in WAT may be pivotal for the beneficial effects of CR.To investigate the involvement of Srebp-1c in CR effects in detail, we used Srebp-1c wild-type (WT) and knockout mice (KO) fed ad libitum (AL) or subjected to CR.First, we confirmed CR-associated induction of Srebp-1c mRNA in WAT of both fed and fasted mice.Moreover, CR upregulated proteins implicated in FA biosynthesis, including fatty acid synthase (Fasn), acetyl-CoA carboxylase (Acc), ATP citrate lyase (Acly), and malic enzyme-1 (Me-1), in WAT of WT.