Srebp-1c/Fgf21/Pgc-1α axis regulated by leptin signaling in adipocytes—possible mechanism of caloric restriction-associated metabolic remodeling of white adipose tissue

Masaki Kobayashi, Seira Uta, Minami Otsubo, Yusuke Deguchi, Ryoma Tagawa, Yuhei Mizunoe, Yoshimi Nakagawa, Hitoshi Shimano, Yoshikazu Higami

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Caloric restriction (CR) improves whole body metabolism, suppresses age-related pathophysiology, and extends lifespan in rodents. Metabolic remodeling, including fatty acid (FA) biosynthesis and mitochondrial biogenesis, in white adipose tissue (WAT) plays an important role in the beneficial effects of CR. We have proposed that CR-induced mitochondrial biogenesis in WAT is mediated by peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), which is transcriptionally regulated by sterol regulatory element-binding protein 1c (SREBP-1c), a master regulator of FA biosynthesis. We have also proposed that the CR-associated upregulation of SREBP1 and PGC-1α might result from the attenuation of leptin signaling and the upregulation of fibroblast growth factor 21 (FGF21) in WAT. However, the detailed molecular mechanisms remain unclear. Here, we interrogate the regulatory mechanisms involving leptin signaling, SREBP-1c, FGF21, and PGC-1α using Srebp-1c knockout (KO) mice, mouse embryonic fibroblasts, and 3T3-L1 adipocytes, by altering the expression of SREBP-1c or FGF21. We show that a reduction in leptin signaling induces the expression of proteins involved in FA biosynthesis and mitochondrial biogenesis via SREBP-1c in adipocytes. The upregulation of SREBP-1c activates PGC-1α transcription via FGF21, but it is unlikely that the FGF21-associated upregulation of PGC-1α expression is a predominant contributor to mitochondrial biogenesis in adipocytes.

Original languageEnglish
Article number2054
Pages (from-to)1-15
Number of pages15
JournalNutrients
Volume12
Issue number7
DOIs
Publication statusPublished - Jul 2020

Keywords

  • Adipocyte
  • Caloric restriction
  • Fatty acid biosynthesis
  • Mitochondrial biogenesis

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