title: A novel role for the Wnt inhibitor APCDD1 in adipocyte differentiation: Implications for diet-induced obesity.
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 differentiationin vitroMechanistically, 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.
authors.affiliation: From the Departments of Pharmacology and Toxicology.|Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.
authors.forename: Nicole K H
authors.initials: NKH
authors.lastname: Yiew
authors.affiliation: Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.|Medicine, Division of Cardiology.
authors.forename: Tapan K
authors.initials: TK
authors.lastname: Chatterjee
authors.affiliation: Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.|Medicine, Division of Cardiology.
authors.forename: Yao Liang
authors.initials: YL
authors.lastname: Tang
authors.affiliation: Pediatrics.
authors.forename: Rod
authors.initials: R
authors.lastname: Pellenberg
authors.affiliation: Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.|Pediatrics.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Stansfield
authors.affiliation: Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.|Medicine, Division of Cardiology.
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bagi
authors.affiliation: From the Departments of Pharmacology and Toxicology.|Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.
authors.forename: David J
authors.initials: DJ
authors.lastname: Fulton
authors.affiliation: Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912.|Physiology.
authors.forename: David W
authors.initials: DW
authors.lastname: Stepp
authors.affiliation: Physiology.
authors.forename: Weiqin
authors.initials: W
authors.lastname: Chen
authors.affiliation: Cardiothoracic and Vascular Surgery, and.
authors.forename: Vijay
authors.initials: V
authors.lastname: Patel
authors.affiliation: Cardiothoracic and Vascular Surgery, and.
authors.forename: Vinayak M
authors.initials: VM
authors.lastname: Kamath
authors.affiliation: the Department of Medicine, Division of Cardiology, Medical University of South Carolina, Charleston, South Carolina 29425.
authors.forename: Sheldon E
authors.initials: SE
authors.lastname: Litwin
authors.affiliation: the Department of Pathology and Lab Medicine, University of Cincinnati, Cincinnati, Ohio 45219, and.
authors.forename: David Y
authors.initials: DY
authors.lastname: Hui
authors.affiliation: Gift of Life Michigan, Ann Arbor, Michigan 48108.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Rudich
authors.affiliation: Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912, hkim3@augusta.edu.|Medicine, Division of Cardiology.
authors.forename: Ha Won
authors.initials: HW
authors.lastname: Kim
authors.affiliation: Vascular Biology Center, Medical College of Georgia at Augusta University, Augusta, Georgia 30912, nweintraub@augusta.edu.|Medicine, Division of Cardiology.
authors.forename: Neal L
authors.initials: NL
authors.lastname: Weintraub
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D004032:Diet / Q000009:adverse effects; D005260:Female; D020868:Gene Silencing; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics; D051379:Mice; D009765:Obesity / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: C549624:APCDD1 protein, human; C498341:Apcdd1 protein, mouse; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C530718:CEBPA protein, mouse; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins
keywords: APCDD1; Wnt signaling; adipocyte; adipose tissue; differentiation; miR-130; obesity