SMP30-mediated synthesis of vitamin C activates the liver PPAR alpha/FGF21 axis to regulate thermogenesis in mice

Abstract

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 PPAR alpha to upregulate FGF21. Our findings demonstrate that SMP30-mediated synthesis of vitamin C activates the PPAR alpha/FGF21 axis, contributing to the maintenance of thermogenesis in mice. Metabolism: Vitamin C synthesis enzyme linked to heat production An enzyme involved in vitamin C synthesis also mediates the ability of mice to generate heat in response to cold exposures. Hae Young Chung from Pusan National University in Busan, South Korea, and colleagues showed that mice without a working version of this enzyme, known as SMP30, do not lose weight under cold conditions. That's because they cannot burn brown fat to create heat through a process called thermogenesis. The researchers detailed how vitamin C, whether produced naturally by SMP30-related signaling in mouse tissues or given via dietary supplement, triggers the activation of signaling molecules and growth factors necessary for thermogenesis. Since humans cannot synthesize their own vitamin C, and thus cannot take advantage of this heat-generating and fat-burning pathway, these findings may help explain a common cause of weight gain and obesity.