Fig. 8: Hypothetical models describing the differences in FGF21/thermogenic signaling between normal and SMP30-deficient conditions.

a The vitamin C-synthesizing enzyme SMP30 is highly expressed in the liver. SMP30-induced synthesis of vitamin C can activate PPARα in the livers of mice, leading to the secretion of FGF21. Then, FGF21 can go to the adipose tissue to elevate thermogenesis and regulate lipid metabolism. b On the other hand, SMP30 deficiency leads to impairment of the vitamin C/PPARα/FGF21 pathway in hepatocytes. Thus, the notable reduction in FGF21 in the blood contributes to the impairment in thermogenic energy expenditure in adipocytes. However, it should be noted that other mechanisms underlying vitamin C-mediated thermogenesis may also exist independent of FGF21 because vitamin C is involved in the synthesis of catecholamines, which are strong thermogenic inducers, and PPARα activated by vitamin C may also induce thermogenic signaling pathways (see the “Discussion” section for detailed information).