Metabolic Alteration in Aging Process: Metabolic Remodeling in White Adipose Tissue by Caloric Restriction

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  • Kobayashi Masaki
    Laboratory of Molecular Pathology and Metabolic Disease, Department of Medical and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science
  • Higami Yoshikazu
    Laboratory of Molecular Pathology and Metabolic Disease, Department of Medical and Life Science, Faculty of Pharmaceutical Sciences, Tokyo University of Science

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Other Title
  • 代謝の老化：カロリー制限による脂肪組織での代謝リモデリング
  • Symposium Review 代謝の老化・カロリー制限による脂肪組織での代謝リモデリング
  • Symposium Review タイシャ ノ ロウカ ・ カロリー セイゲン ニ ヨル シボウ ソシキ デ ノ タイシャ リモデリング

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Abstract

<p>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.</p>

Journal

  • YAKUGAKU ZASSHI

    YAKUGAKU ZASSHI 140 (3), 383-389, 2020-03-01

    The Pharmaceutical Society of Japan

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