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Srebp-1c/Fgf21/Pgc-1α Axis Regulated by Leptin Signaling in Adipocytes—Possible Mechanism of Caloric Restriction-Associated Metabolic Remodeling of White Adipose Tissue

1
Laboratory of Molecular Pathology and Metabolic Disease, Faculty of Pharmaceutical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
2
Department of Internal Medicine (Endocrinology and Metabolism), Faculty of Medicine, University of Tsukuba, Ibaraki 305-8575, Japan
3
Division of Complex Biosystem Research, Department of Research and Development, Institute of Natural Medicine, University of Toyama, Toyama 930-0194, Japan
4
Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Ibaraki 305-8575, Japan
5
AMED-CREST, Japan Agency for Medical Research and Development (AMED), Tokyo 100-1004, Japan
6
Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba 278-8510, Japan
*
Author to whom correspondence should be addressed.
Nutrients 2020, 12(7), 2054; https://doi.org/10.3390/nu12072054
Received: 6 June 2020 / Revised: 4 July 2020 / Accepted: 8 July 2020 / Published: 10 July 2020
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 SREBP-1 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. View Full-Text
Keywords: caloric restriction; fatty acid biosynthesis; mitochondrial biogenesis; adipocyte caloric restriction; fatty acid biosynthesis; mitochondrial biogenesis; adipocyte
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Kobayashi, M.; Uta, S.; Otsubo, M.; Deguchi, Y.; Tagawa, R.; Mizunoe, Y.; Nakagawa, Y.; Shimano, H.; Higami, Y. Srebp-1c/Fgf21/Pgc-1α Axis Regulated by Leptin Signaling in Adipocytes—Possible Mechanism of Caloric Restriction-Associated Metabolic Remodeling of White Adipose Tissue. Nutrients 2020, 12, 2054.

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