2. Academic Validation
  3. The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2

The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2

  • Antioxidants (Basel). 2023 Jan 5;12(1):133. doi: 10.3390/antiox12010133.
Yoshiki Higa 1 2,  Masahiro Hiasa 1,  Hirofumi Tenshin 1,  Emiko Nakaue 1,  Mariko Tanaka 1,  Sooha Kim 1,  Motosumi Nakagawa 1,  So Shimizu 1,  Kotaro Tanimoto 1,  Jumpei Teramachi 3,  Takeshi Harada 2,  Asuka Oda 2,  Masahiro Oura 2,  Kimiko Sogabe 2,  Tomoyo Hara 2,  Ryohei Sumitani 2,  Tomoko Maruhashi 2,  Hiroki Yamagami 2,  Itsuro Endo 4,  Toshio Matsumoto 5,  Eiji Tanaka 1,  Masahiro Abe 2
Affiliations

Affiliations

  • 1 Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
  • 2 Department of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
  • 3 Department of Oral Function and Anatomy, Graduate School of Medicine Dentistry and Pharmaceutical Sciences, Okayama University, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8530, Japan.
  • 4 Department of Bioregulatory Sciences, Graduate School of Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
  • 5 Fujii Memorial Institute of Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, Japan.
PMID: 36670994 DOI: 10.3390/antiox12010133
Abstract

Xanthine oxidoreductase (XOR) is a rate-limiting enzyme in purine catabolism that acts as a novel regulator of adipogenesis. In pathological states, xanthine oxidoreductase activity increases to produce excess Reactive Oxygen Species (ROS). The nuclear factor erythroid 2-related factor 2 (Nrf2) is a critical inducer of Antioxidants, which is bound and repressed by a kelch-like ECH-associated protein 1 (Keap1) in the cytoplasm. The Keap1-Nrf2 axis appears to be a major mechanism for robust inducible antioxidant defenses. Here, we demonstrate that febuxostat, a Xanthine Oxidase Inhibitor, alleviates the increase in adipose tissue mass in obese mouse models with a high-fat diet or ovariectomy. Febuxostat disrupts in vitro adipocytic differentiation in adipogenic media. Adipocytes appeared at day 7 in absence or presence of febuxostat were 160.8 ± 21.2 vs. 52.5 ± 12.7 (p < 0.01) in 3T3−L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (p < 0.01) in 10T1/2 cells, respectively. Adipocyte differentiation was further enhanced by the addition of hydrogen peroxide, which was also suppressed by febuxostat. Interestingly, febuxostat, but not allopurinol (another Xanthine Oxidase Inhibitor), rapidly induced the nuclear translocation of Nrf2 and facilitated the degradation of Keap1, similar to the electrophilic Nrf2 activator omaveloxolone. These results suggest that febuxostat alleviates adipogenesis under oxidative conditions, at least in part by suppressing ROS production and Nrf2 activation. Regulation of adipocytic differentiation by febuxostat is expected to inhibit obesity due to menopause or overeating.

Keywords

Keap1; Nrf2; adipocytic differentiation; febuxostat; obesity; reactive oxygen species (ROS); xanthine oxidoreductase (XOR).

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