Abstract 18952: Mir-130 Targets Apcdd1 Expression to Inhibit Adipocyte Differentiation: Role in Diet-Induced Obesity
Background: Impaired adipocyte differentiation during diet-induced obesity (DIO) promotes adipocyte hypertrophy and inflammation, thereby contributing to cardiometabolic disease. We recently reported that adenomatosis polyposis coli downregulated 1 (APCDD1) stimulates adipocyte differentiation by repressing Wnt signaling. Here, we examined the impact of high fat diet (HFD) on adipocyte differentiation and APCDD1 expression and uncovered a novel epigenetic regulatory mechanism involving miR-130 that may contribute to the pathogenesis of DIO.
Methods and Results: 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 preadipocytes markedly increased Wnt signaling (Wnt, LRP5, β-catenin) and inhibited adipocyte gene (C/EBPα, PPARγ) expression and lipid droplet accumulation, while adenoviral-mediated overexpression of APCDD1 enhanced adipocyte differentiation. Notably, 12 weeks of HFD in mice significantly reduced APCDD1 gene expression (~10 fold) in subcutaneous adipose tissues and blocked adipocyte differentiation in vitro, suggesting an epigenetic regulatory mechanism. miR-130 was predicted to directly target the 3’-untranslated region of APCDD1 mRNA. Intriguingly, miR-130 expression was significantly upregulated in adipose tissues isolated from HFD mice. Furthermore, transfection of miR-130 inhibitor in preadipocytes enhanced, while miR-130 mimic abolished, adipocyte differentiation, suggesting that miR-130 contributes to impaired adipocyte differentiation during DIO by repressing APCDD1 expression. To investigate the relevance of APCDD1 in human obesity, we examined the expression levels of APCDD1 in adipose tissues from non-obese and obese subjects and found that APCDD1 expression in human adipose tissues was significantly lower in obese subjects (~50%), in conjunction with downregulation of C/EBPα, PPARγ and upregulation of Wnt expression.
Conclusions: Upregulated expression of miR-130 in adipose tissues during DIO represses APCDD1 expression and may contribute to impaired adipocyte differentiation and obesity-related cardiometabolic disease.
Author Disclosures: H. Kim: None. K. Yiew: None. R. Pellenberg: None. T.K. Chatterjee: None. Y. Tang: None. Z. Bagi: None. V. Patel: None. D. Hui: None. N.L. Weintraub: None.
- © 2016 by American Heart Association, Inc.