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Long-term caloric restriction (CR) is an effective intervention that improves whole-body metabolism, suppresses age-related pathophysiology, and extends lifespan. Although the beneficial effects of caloric restriction mediated by growth hormone/insulin-like growth factor-1 (GH/IGF-1) have been extensively studied, the mechanisms independent of GH/IGF-1 remain largely unknown. In this review, we focus on these GH/IGF-1-independent mechanisms, with a particular emphasis on the role of sterol regulatory element-binding protein 1c (SREBP-1c). CR increases the expression of SREBP-1c through the suppression of leptin signaling and enhances downstream factors involved in fatty acid synthesis in white adipose tissue (WAT). SREBP-1c also directly and indirectly increases the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, a master regulator of mitochondrial biogenesis, leading to an increase in the number of mitochondria. Furthermore, SREBP-1c elevates expression of mitochondrial intermediate peptidase, which contributes to improving mitochondrial quality through the processing of sirtuin 3 into its mature form. Thus, it appears that CR exerts beneficial effects by modulating mitochondrial quantity and quality in WAT in a GH/IGF-1 signal-independent manner.

Caloric restriction (CR) improves whole-body metabolism, suppresses various age-related pathophysiological changes, and extends lifespan. The beneficial actions of CR are regulated in growth hormone (GH)/insulin-like growth factor-1 (IGF-1) signal-dependent and -independent manners. To clarify the GH/IGF-1-independent mechanism, we compared gene expression profiles in white adipose tissue (WAT) between CR and GH/IGF-1 suppression, and found that CR upregulated sterol regulatory element-binding protein 1c (SREBP-1c) regulatory gene expression. To validate the impact of SREBP-1c as a beneficial mediator of CR, we compared the responses to CR between wild-type and SREBP-1c knockout (KO) mice. CR extended lifespan, upregulated gene expression involved in FA biosynthesis, activated mitochondrial biogenesis, and suppressed oxidative stress predominantly in WAT. In contrast, most of these findings were not observed in KO mice. Furthermore, SREBP-1c was implicated in CR-associated mitochondrial activation through upregulation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), a master regulator of mitochondrial biogenesis. Sirtuin-3 (SIRT3) regulates mitochondrial quality and is also involved in the beneficial actions of CR. We observed that CR upregulated the mature form of SIRT3 protein and mitochondrial intermediate peptidase (MIPEP), a mitochondrial signal peptidase (MtSPase), in WAT. MIPEP cleaved precursor form of SIRT3 to mature form, and activated certain mitochondrial matrix proteins, suggesting that MIPEP might contribute to maintenance of mitochondrial quality during CR via SIRT3 activation. Taken together, CR induces SREBP-1c-dependent metabolic remodeling, including enhancement of FA biosynthesis and mitochondrial activation, via PGC-1α, and improvement of mitochondria quality via Mipep in WAT, resulting in beneficial actions.