Article | Published:

Adipocyte and Cell Biology

Regulation of PKCβ levels and autophagy by PML is essential for high-glucose-dependent mesenchymal stem cell adipogenesis

International Journal of Obesity (2018) | Download Citation

Abstract

Background/Objectives

Obesity is a complex disease characterized by the accumulation of excess body fat, which is caused by an increase in adipose cell size and number. The major source of adipocytes comes from mesenchymal stem cells (MSCs), although their roles in obesity remain unclear. An understanding of the mechanisms, regulation, and outcomes of adipogenesis is crucial for the development of new treatments for obesity-related diseases. Recently an unexpected role for the tumor suppressor promyelocytic leukemia protein (PML) in hematopoietic stem cell biology and metabolism regulation has come to light, but its role in MSC biology remains unknown. Here, we investigated the molecular pathway underlying the role of PML in the control of adipogenic MSC differentiation.

Subjects/Methods

Muscle-derived stem cells (MDSCs) and adipose-derived stem cells (ADSCs) obtained from mice and voluntary patients (as a source of MSCs) were cultured in the presence of high glucose (HG) concentration, a nutrient stress condition known to promote MSCs differentiation into mature adipocytes and the adipogenic potential of PML was assessed.

Results

PML is essential for a correct HG-dependent adipogenic differentiation, and the enhancement of PML levels is fundamental during adipogenesis. Increased PML expression enables the upregulation of protein kinase Cβ (PKCβ), which, in turn, by controlling autophagy levels permits an increase in peroxisome proliferator-activated receptor γ (PPARγ) that leads the adipogenic differentiation. Therefore, genetic and pharmacological depletion of PML prevents PKCβ expression, and by increasing autophagy levels, impairs the MSCs adipogenic differentiation. Human ADSCs isolated from overweight patients displayed increased PML and PKCβ levels compared to those found in normal weight individuals, indicating that the PML-PKCβ pathway is directly involved in the enhancement of adipogenesis and human metabolism.

Conclusions

The new link found among PML, PKCβ, and autophagy opens new therapeutic avenues for diseases characterized by an imbalance in the MSCs differentiation process, such as metabolic syndromes and cancer.

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Acknowledgements

CG is supported by local funds from the University of Ferrara, the Italian Association for Cancer Research, the Italian Ministry of Health, and by Cariplo grant. MRW is supported by the FOIE GRAS and mtFOIE GRAS projects.These projects received funding from the European Union’sHorizon 2020 Research and Innovation programme under the MarieSkłodowska-Curie Grant Agreement No. 722619 (FOIE GRAS) andGrant Agreement No. 734719 (mtFOIE GRAS).

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Affiliations

  1. Department of Morphology, Surgery and Experimental Medicine, Section of General Pathology and Laboratory for Technologies of Advanced Therapies (LTTA), University of Ferrara, Ferrara, Italy

    • Claudia Morganti
    • , Sonia Missiroli
    • , Magdalena Lebiedzinska-Arciszewska
    • , Mariasole Perrone
    • , Daniela Ramaccini
    •  & Carlotta Giorgi
  2. Nencki Institute of Experimental Biology PAS, Warsaw, Poland

    • Magdalena Lebiedzinska-Arciszewska
    •  & Mariusz R. Wieckowski
  3. Department of Biomedical Sciences, University of Padova, Padova, Italy

    • Letizia Ferroni
    •  & Barbara Zavan
  4. Department of Morphology, Surgery and Experimental Medicine, Acute Care Surgery Service, University of Ferrara and S.Anna University Hospital of Ferrara, Ferrara, Italy

    • Lucia Morganti
    •  & Savino Occhionorelli

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Conflict of interest

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Carlotta Giorgi.

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DOI

https://doi.org/10.1038/s41366-018-0167-1