title: Knockdown of PTRF ameliorates adipocyte differentiation and functionality of human mesenchymal stem cells.
abstract: Healthy expansion of human adipose tissue requires mesenchymal stem cells (hMSC) able to proliferate and differentiate into mature adipocytes. Hence, characterization of those factors that coordinate hMSC-to-adipocyte transition is of paramount importance to modulate the adipose tissue expansion. It has been previously reported that the adipogenic program of hMSC can be disrupted by upregulating caveolar proteins, and polymerase I and transcript release factor (PTRF) is an integral component of caveolae, highly expressed in adipose tissue. Here, we hypothesized that the role of PTRF in adipocyte functionality might stem from an effect on hMSC. To test this hypothesis, we isolated hMSC from the subcutaneous fat depot. We found an upregulated expression of the PTRF associated with decreased adipogenic potential of hMSC, likely due to the existence of senescent adipocyte precursors. Employing short hairpin RNA-based constructs to stably reduce PTRF, we were able to restore insulin sensitivity and reduced basal lipolysis and leptin levels in human adipocytes with high levels of PTRF. Additionally, we pinpointed the detrimental effect caused by PTRF on the adipose tissue to the existence of senescent adipocyte precursors unable to proliferate and differentiate into adipocytes. This study provides evidence that impaired adipocyte functionality can be corrected, at least partially, by PTRF downregulation and warrants further in vivo research in patients with dysfunctional adipose tissue to prevent metabolic complications.
authors.affiliation: Adipocyte and Fat Biology Laboratory (AdipoFat), Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (IACS), Instituto de Investigación Sanitaria (IIS) Aragón, Zaragoza, Spain.
authors.forename: Sergio
authors.initials: S
authors.lastname: Perez-Diaz
authors.affiliation: Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors.forename: Beatriz
authors.initials: B
authors.lastname: Garcia-Rodriguez
authors.affiliation: Servicio de Bioquímica Clínica, Hospital Universitario Miguel Servet, Zaragoza, Spain.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Gonzalez-Irazabal
authors.affiliation: Unidad de Cirugía, Hospital Royo Villanova, Zaragoza, Spain; and.
authors.forename: Monica
authors.initials: M
authors.lastname: Valero
authors.affiliation: Unidad de Cirugía, Hospital Royo Villanova, Zaragoza, Spain; and.
authors.forename: Javier
authors.initials: J
authors.lastname: Lagos-Lizan
authors.affiliation: Adipocyte and Fat Biology Laboratory (AdipoFat), Unidad de Investigación Traslacional, Hospital Universitario Miguel Servet, Instituto Aragonés de Ciencias de la Salud (IACS), Instituto de Investigación Sanitaria (IIS) Aragón, Zaragoza, Spain; jmarbones.iacs@aragon.es.|CIBER Fisiopatología Obesidad y Nutrición (CIBERObn), Instituto Salud Carlos III, Madrid, Spain.
authors.forename: Jose M
authors.identifier: http://orcid.org/0000-0002-8982-3737
authors.initials: JM
authors.lastname: Arbones-Mainar
mesh_terms: D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism*; D050156:Adipogenesis / Q000502:physiology; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000502:physiology*; D008875:Middle Aged; D016601:RNA-Binding Proteins / Q000378:metabolism*
chemical_list: C497835:CAVIN1 protein, human; D016601:RNA-Binding Proteins
keywords: adipose; lentiviral; loss of function; senescence