Novel role for Wnt inhibitor APCDD1 in adipocyte differentiation: implications for diet-induced obesity [Lipids]

Impaired adipogenic differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to metabolic disease. Adenomatosis polyposis coli downregulated 1 (APCDD1) has recently been identified as an inhibitor of Wnt signaling, a key regulator of adipogenic differentiation. Here, we report a novel role for APCDD1 in adipogenic differentiation via repression of Wnt signaling, and an epigenetic linkage between miR-130 and APCDD1 in DIO. APCDD1 expression was significantly upregulated in mature adipocytes as compared to undifferentiated preadipocytes in both human and mouse subcutaneous adipose tissues. siRNA-based silencing of APCDD1 in 3T3-L1 preadipocytes markedly increased expression of Wnt signaling proteins (Wnt3a, Wnt5a, Wnt10b, LRP5, β-catenin), and inhibited expression of adipocyte differentiation markers (C/EBPα, PPARγ and lipid droplet accumulation, while adenovirus-mediated overexpression of APCDD1 enhanced adipogenic differentiation. Notably, DIO mice exhibited reduced APCDD1 expression and increased Wnt expression in both subcutaneous and visceral adipose tissues and impaired adipogenic differentiation in vitro. Mechanistically, we found that miR-130, whose expression is upregulated in adipose tissues of DIO mice, could directly target the 3′-untranslated region of the APCDD1 gene. Furthermore, transfection of a miR-130 inhibitor in preadipocytes enhanced, while a miR-130 mimic blunted, adipogenic differentiation, suggesting that miR-130 contributes to impaired adipogenic differentiation during DIO by repressing APCDD1 expression. Finally, human subcutaneous adipose tissues isolated from obese individuals exhibited reduced expression of APCDD1, C/EBPα and PPARγ as compared to those from non-obese subjects. Taken together, these novel findings suggest that APCDD1 positively regulates adipogenic differentiation, and that its downregulation by miR-130 during DIO may contribute to impaired adipogenic differentiation and obesity-related metabolic disease.

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