Abstract
Impaired adipogenic differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to metabolic disease. Adenomatosis polyposis coli down-regulated 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 up-regulated in mature adipocytes compared with undifferentiated preadipocytes in both human and mouse subcutaneous adipose tissues. siRNA-based silencing of APCDD1 in 3T3-L1 preadipocytes markedly increased the expression of Wnt signaling proteins (Wnt3a, Wnt5a, Wnt10b, LRP5, and β-catenin) and inhibited the expression of adipocyte differentiation markers (CCAAT/enhancer-binding protein α (C/EBPα) and peroxisome proliferator-activated receptor γ (PPARγ)) and lipid droplet accumulation, whereas 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 up-regulated in adipose tissues of DIO mice, could directly target the 3'-untranslated region of the APCDD1 gene. Furthermore, transfection of an miR-130 inhibitor in preadipocytes enhanced, whereas an 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 compared with those from non-obese subjects. Taken together, these novel findings suggest that APCDD1 positively regulates adipogenic differentiation and that its down-regulation by miR-130 during DIO may contribute to impaired adipogenic differentiation and obesity-related metabolic disease.
Highlights
To examine whether Adenomatosis polyposis coli down-regulated 1 (APCDD1) is differentially expressed in mature adipocytes versus undifferentiated preadipocytes (PA), we fractionated human subcutaneous adipose tissues to obtain floating mature adipocytes and the stromal vascular fraction, which is enriched in preadipocytes
Time course experiments in mouse 3T3-L1 preadipocytes demonstrated that APCDD1 mRNA expression is rapidly induced following the onset of adipogenic differentiation, with levels peaking by day 3 and sustained for up to 12 days (Fig. 1D)
APCDD1 is weakly expressed in subcutaneous adipose tissues isolated from obese mice and humans, consistent with reports of impaired adipocyte differentiation in diet-induced obesity (DIO)
Summary
Wnt expression was reported to be down-regulated during differentiation of murine preadipocytes [18]. APCDD1 gene silencing increased the expression of proteins associated with the Wnt/catenin signaling pathway, including Wnt3a, Wnt5a, Wnt10b, LRP5, and -catenin, in 3T3-L1 preadipocytes (Fig. 2, B and C). These data indicate that knockdown of APCDD1 blocks adipogenic differentiation while up-regulating Wnt signaling. At 7 days of adipogenic differentiation, APCDD1-overexpressing cells exhibited increased lipid droplet accumulation (Fig. 3A) and adipogenic marker (adiponectin, FABP4, C/EBP␣, and PPAR␥) expression (Fig. 3, B and C) compared with GFP control-transduced cells. The expression of Wnt signaling proteins, including Wnt3a, Wnt5a, LRP5, and -catenin, was attenuated in APCDD1overexpressing cells compared with the control These findings suggest that APCDD1 positively regulates adipogenic differentiation while suppressing the Wnt signaling pathway
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