title: Androgens inhibit adipogenesis during human adipose stem cell commitment to preadipocyte formation.
abstract: Androgens play a pivotal role in the regulation of body fat distribution. Adipogenesis is a process whereby multipotent adipose stem cells (ASCs) initially become preadipocytes (ASC commitment to preadipocytes) before differentiating into adipocytes. Androgens inhibit human (h) subcutaneous (SC) abdominal preadipocyte differentiation in both sexes, but their effects on hASC commitment to preadipocyte formation is unknown. We therefore examined whether androgen exposure to human (h) ASCs, isolated from SC abdominal adipose of nonobese women, impairs their commitment to preadipocyte formation and/or subsequent differentiation into adipocytes. For this, isolated hASCs from SC abdominal lipoaspirate were cultured in adipogenesis-inducing medium for 0.5-14days in the presence of testosterone (T, 0-100nM) or dihydrotestosterone (DHT, 0-50nM). Adipogenesis was determined by immunofluorescence microscopy and by quantification of adipogenically relevant transcriptional factors, PPARγ, C/EBPα and C/EBPβ. We found that a 3-day exposure of hASCs to T (50nM) or DHT (5nM) in adipogenesis-inducing medium impaired lipid acquisition and decreased PPARγ, C/EBPα and C/EBPβ gene expression. The inhibitory effects of T and DHT at this early-stage of adipocyte differentiation, were partially and completely reversed by flutamide (F, 100nM), respectively. The effect of androgens on hASC commitment to a preadipocyte phenotype was examined via activation of Bone Morphogenic Protein 4 (BMP4) signaling. T (50nM) and DHT (5nM) significantly inhibited the stimulatory effect of BMP4-induced ASC commitment to the preadipocyte phenotype, as regards PPARγ and C/EBPα gene expression. Our findings indicate that androgens, in part through androgen receptor action, impair BMP4-induced commitment of SC hASCs to preadipocytes and also reduce early-stage adipocyte differentiation, perhaps limiting adipocyte numbers and fat storage in SC abdominal adipose.
authors.affiliation: Department of Obstetrics and Gynecology, David Geffen School of Medicine at UCLA, Los Angeles, CA, United States. gchazenbalk@mednet.ucla.edu
authors.forename: Gregorio
authors.initials: G
authors.lastname: Chazenbalk
authors.forename: Prapti
authors.initials: P
authors.lastname: Singh
authors.forename: Dana
authors.initials: D
authors.lastname: Irge
authors.forename: Amy
authors.initials: A
authors.lastname: Shah
authors.forename: David H
authors.initials: DH
authors.lastname: Abbott
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Dumesic
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D050156:Adipogenesis; D053687:Adult Stem Cells / Q000502:physiology*; D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology / Q000502:physiology*; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000235:genetics / Q000378:metabolism; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D013196:Dihydrotestosterone / Q000494:pharmacology*; D005260:Female; D005485:Flutamide / Q000494:pharmacology; D015870:Gene Expression; D006801:Humans; D050356:Lipid Metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism; D015398:Signal Transduction; D013739:Testosterone / Q000494:pharmacology / Q000502:physiology*
chemical_list: D000726:Androgen Antagonists; D000728:Androgens; C525809:BMP4 protein, human; D055415:Bone Morphogenetic Protein 4; D022782:CCAAT-Enhancer-Binding Protein-beta; D022762:CCAAT-Enhancer-Binding Proteins; C515848:CEBPA protein, human; C545012:CEBPB protein, human; D047495:PPAR gamma; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D013739:Testosterone; D005485:Flutamide
keywords: Adipogenesis; Cell commitment; Dihydrotestosterone; Testosterone