The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2
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...
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MDPI AG
2023-01-01
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| Series: | Antioxidants |
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| author | Yoshiki Higa Masahiro Hiasa Hirofumi Tenshin Emiko Nakaue Mariko Tanaka Sooha Kim Motosumi Nakagawa So Shimizu Kotaro Tanimoto Jumpei Teramachi Takeshi Harada Asuka Oda Masahiro Oura Kimiko Sogabe Tomoyo Hara Ryohei Sumitani Tomoko Maruhashi Hiroki Yamagami Itsuro Endo Toshio Matsumoto Eiji Tanaka Masahiro Abe |
| author_facet | Yoshiki Higa Masahiro Hiasa Hirofumi Tenshin Emiko Nakaue Mariko Tanaka Sooha Kim Motosumi Nakagawa So Shimizu Kotaro Tanimoto Jumpei Teramachi Takeshi Harada Asuka Oda Masahiro Oura Kimiko Sogabe Tomoyo Hara Ryohei Sumitani Tomoko Maruhashi Hiroki Yamagami Itsuro Endo Toshio Matsumoto Eiji Tanaka Masahiro Abe |
| author_sort | Yoshiki Higa |
| collection | DOAJ |
| description | 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 (<i>p</i> < 0.01) in 3T3–L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (<i>p</i> < 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. |
| first_indexed | 2024-03-09T13:45:53Z |
| format | Article |
| id | doaj.art-1a8368b762724ac5baaade1b3f73a634 |
| institution | Directory Open Access Journal |
| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-09T13:45:53Z |
| publishDate | 2023-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Antioxidants |
| spelling | doaj.art-1a8368b762724ac5baaade1b3f73a6342023-11-30T20:58:47ZengMDPI AGAntioxidants2076-39212023-01-0112113310.3390/antiox12010133The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2Yoshiki Higa0Masahiro Hiasa1Hirofumi Tenshin2Emiko Nakaue3Mariko Tanaka4Sooha Kim5Motosumi Nakagawa6So Shimizu7Kotaro Tanimoto8Jumpei Teramachi9Takeshi Harada10Asuka Oda11Masahiro Oura12Kimiko Sogabe13Tomoyo Hara14Ryohei Sumitani15Tomoko Maruhashi16Hiroki Yamagami17Itsuro Endo18Toshio Matsumoto19Eiji Tanaka20Masahiro Abe21Department of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment 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, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Bioregulatory Sciences, Graduate School of Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanFujii Memorial Institute of Medical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Orthodontics and Dentofacial Orthopedics, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanDepartment of Hematology, Endocrinology and Metabolism, Graduate School of Biomedical Sciences, Tokushima University, 3-18-15 Kuramoto, Tokushima 770-8503, JapanXanthine 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 (<i>p</i> < 0.01) in 3T3–L1 cells, and 126.0 ± 18.7 vs. 55.3 ± 13.4 (<i>p</i> < 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.https://www.mdpi.com/2076-3921/12/1/133obesityadipocytic differentiationreactive oxygen species (ROS)xanthine oxidoreductase (XOR)febuxostatNrf2 |
| spellingShingle | Yoshiki Higa Masahiro Hiasa Hirofumi Tenshin Emiko Nakaue Mariko Tanaka Sooha Kim Motosumi Nakagawa So Shimizu Kotaro Tanimoto Jumpei Teramachi Takeshi Harada Asuka Oda Masahiro Oura Kimiko Sogabe Tomoyo Hara Ryohei Sumitani Tomoko Maruhashi Hiroki Yamagami Itsuro Endo Toshio Matsumoto Eiji Tanaka Masahiro Abe The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2 Antioxidants obesity adipocytic differentiation reactive oxygen species (ROS) xanthine oxidoreductase (XOR) febuxostat Nrf2 |
| title | The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2 |
| title_full | The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2 |
| title_fullStr | The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2 |
| title_full_unstemmed | The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2 |
| title_short | The Xanthine Oxidase Inhibitor Febuxostat Suppresses Adipogenesis and Activates Nrf2 |
| title_sort | xanthine oxidase inhibitor febuxostat suppresses adipogenesis and activates nrf2 |
| topic | obesity adipocytic differentiation reactive oxygen species (ROS) xanthine oxidoreductase (XOR) febuxostat Nrf2 |
| url | https://www.mdpi.com/2076-3921/12/1/133 |
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