Anti-adipogenic effects of 1,25-dihydroxyvitamin D3 are mediated by the maintenance of the wingless-type MMTV integration site/β-catenin pathway

Abstract

1,25-dihydroxyvitamin D3 (1,25(OH)2D3), the active metabolite of vitamin D, was found to have anti-adipogenic activity, however, its mechanism of action has not been fully elucidated. In this study, 3T3-L1 preadipocytes were differentiated in the presence and absence of 1,25(OH)2D3, and the expression of the genes and proteins of the wingless-type MMTV integration site (WNT)/β-catenin pathway were analyzed. While the expression of the members of the WNT/β-catenin pathway were significantly downregulated during the adipogenesis of untreated 3T3-L1 cells, 1,25(OH)2D3 treatment was found to maintain the WNT/β-catenin pathway. Among the members of the WNT/β-catenin pathway, the levels of WNT10B and disheveled (DVL)2 as well as the phosphorylation of glycogen synthase kinase (GSK)3β were maintained by 1,25(OH)2D3 treatment. The levels of nuclear β-catenin, which were downregulated during adipogenesis, were also maintained by 1,25(OH)2D3 treatment. The results of this study suggested that the anti-adipogenic effect of 1,25(OH)2D3 was mediated by the maintenance of the WNT/β-catenin pathway, which was normally downregulated during adipogenesis.

Induction of STEAP4 correlates with 1,25‐dihydroxyvitamin D3 stimulation of adipogenesis in mesenchymal progenitor cells derived from human adipose tissue

“…It should be noted that there are numerous conflicting reports in the literature concerning the effects of 1,25D and its interactions with PPARγ in modulating lipogenesis. For instance, in contrast to the results observed in human cells, 1,25D inhibits adipogenesis in the commonly utilized 3T3‐L1 rodent cell line (Blumberg et al, ; Kong and Li, ; Lee et al, ). In other non‐human models, both stimulation (Bellows et al, ; Zhang et al, ; Mahajan and Stahl, ) and inhibition (Cianferotti and Demay, ) of adipogenesis in response to 1,25D have been reported.…”

Extraskeletal actions of vitamin D

“…The impact of 1,25(OH) 2 D on adipogenesis is dependent on species and level of differentiation of the cell at the time 1,25(OH) 2 D is added to the medium—not unlike the situation in bone, perhaps not surprisingly since adipocytes and osteoblasts can share a common precursor at least in the bone marrow. In particular, 1,25(OH) 2 D promotes adipogenesis from human mesenchymal progenitor cells but is inhibitory in mouse preadipocytes at least in part by inhibiting the expression of inhibitors of Wnt/β‐catenin signaling, thus promoting Wnt/β‐catenin stimulation of osteoblastogenesis rather than adipogenesis. Human fibroblasts with VDR mutations are less likely to differentiate into adipocytes in adipogenic medium than normal fibroblasts .…”

Vitamin D and adipose tissue—more than storage

“…WNT/β-catenin maintain preadipocytes in their undifferentiated state and thus preventing adipogenesis (Ross et al, 2000). The anti-adipogenic effect of 1,25(OH) 2 D 3 is mediated by maintenance of WNT10B and nuclear β-catenin levels expression levels in 3T3-L1 preadipocytes, thereby suppressing transcription factor PPARγ (Lee et al, 2012). In addition, 1,25(OH) 2 D 3 also inhibited mouse bone marrow stromal cells(BMSCs) differentiation into adipocytes by suppression of dickkopf1 (DKK1) and secreted frizzled-related protein 2 (SFRP2) expression levels via VDR mediated WNT signaling (Cianferotti and Demay, 2007).…”