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PNAS 105 (4): 1226-1231

Copyright © 2008 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

High glucose induces adipogenic differentiation of muscle-derived stem cells

Paola Aguiari*, Sara Leo*, Barbara Zavan{dagger}, Vincenzo Vindigni{ddagger}, Alessandro Rimessi*, Katiuscia Bianchi*, Chiara Franzin§, Roberta Cortivo{dagger}, Marco Rossato§, Roberto Vettor§, Giovanni Abatangelo{dagger}, Tullio Pozzan,||, Paolo Pinton*, and Rosario Rizzuto*,||

*Department of Experimental and Diagnostic Medicine, Interdisciplinary Center for the Study of Inflammation, University of Ferrara, 44100 Ferrara, Italy; {dagger}Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, 35122 Padua, Italy; {ddagger}Clinic of Plastic Surgery, University of Padua, 35122 Padua, Italy; §Endocrine-Metabolic Laboratory, Internal Medicine, Department of Medical and Surgical Sciences, University of Padua, 35122 Padua, Italy; and Department of Biomedical Sciences, CNR Institute of Neuroscience, and Venetian Institute of Molecular Medicine, University of Padua, 35122 Padua, Italy

Contributed by Tullio Pozzan, December 5, 2007

Received for publication September 14, 2007.

Abstract: Regeneration of mesenchymal tissues depends on a resident stem cell population, that in most cases remains elusive in terms of cellular identity and differentiation signals. We here show that primary cell cultures derived from adipose tissue or skeletal muscle differentiate into adipocytes when cultured in high glucose. High glucose induces ROS production and PKCβ activation. These two events appear crucial steps in this differentiation process that can be directly induced by oxidizing agents and inhibited by PKCβ siRNA silencing. The differentiated adipocytes, when implanted in vivo, form viable and vascularized adipose tissue. Overall, the data highlight a previously uncharacterized differentiation route triggered by high glucose that drives not only resident stem cells of the adipose tissue but also uncommitted precursors present in muscle cells to form adipose depots. This process may represent a feed-forward cycle between the regional increase in adiposity and insulin resistance that plays a key role in the pathogenesis of diabetes mellitus.

Key Words: adipocyte • hyperglycemia • PKC • ROS

Author contributions: P.A., S.L., and B.Z. contributed equally to this work; P.P. and R.R. designed research; P.A., S.L., B.Z., V.V., A.R., K.B., and C.F. performed research; P.A., S.L., B.Z., A.R., R.C., M.R., R.V., G.A., T.P., and P.P. analyzed data; and R.R. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0711402105/DC1.

||To whom correspondence may be addressed. E-mail: tullio.pozzan{at}unipd.it or rzr{at}unife.it

© 2008 by The National Academy of Sciences of the USA

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