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KMID : 0620920220540112036
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Experimental & Molecular Medicine
2022 Volume.54 No. 11 p.2036 ~ p.2046
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SMP30-mediated synthesis of vitamin C activates the liver PPARα/FGF21 axis to regulate thermogenesis in mice
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Lee Bong-Gi
An Hye-Jin
Kim Dae-Hyun
Lee Min-Kyeong
Jeong Hyeon-Hak
Chung Ki-Wung
Go Young-Hoon
Seo Arnold Y.
Kim Il-Yong
Seong Je-Kyung
Yu Byung-Pal
Lee Jae-Won
Im Eun-Ok
Lee In-Kyu
Lee Myung-Shik
Yamada Ken ichi
Chung Hae-Young
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Abstract
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The vitamin-C-synthesizing enzyme senescent marker protein 30 (SMP30) is a cold resistance gene in Drosophila, and vitamin C concentration increases in brown adipose tissue post-cold exposure. However, the roles of SMP30 in thermogenesis are unknown. Here, we tested the molecular mechanism of thermogenesis using wild-type (WT) and vitamin C-deficient SMP30-knockout (KO) mice. SMP30-KO mice gained more weight than WT mice without a change in food intake in response to short-term high-fat diet feeding. Indirect calorimetry and cold-challenge experiments indicated that energy expenditure is lower in SMP30-KO mice, which is associated with decreased thermogenesis in adipose tissues. Therefore, SMP30-KO mice do not lose weight during cold exposure, whereas WT mice lose weight markedly. Mechanistically, the levels of serum FGF21 were notably lower in SMP30-KO mice, and vitamin C supplementation in SMP30-KO mice recovered FGF21 expression and thermogenesis, with a marked reduction in body weight during cold exposure. Further experiments revealed that vitamin C activates PPARα to upregulate FGF21. Our findings demonstrate that SMP30-mediated synthesis of vitamin C activates the PPARα/FGF21 axis, contributing to the maintenance of thermogenesis in mice.
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