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Targeted delivery of HGF to the skeletal muscle improves glucose homeostasis in diet-induced obese mice

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Abstract

Hepatocyte growth factor (HGF) is a cytokine that increases glucose transport ex vivo in skeletal muscle. The aim of this work was to decipher the impact of whether conditional overexpression of HGF in vivo could improve glucose homeostasis and insulin sensitivity in mouse skeletal muscle. Following tetracyclin administration, muscle HGF levels were augmented threefold in transgenic mice (SK-HGF) compared to control mice without altering plasma HGF levels. In conditions of normal diet, SK-HGF mice showed no differences in body weight, plasma triglycerides, blood glucose, plasma insulin and glucose tolerance compared to control mice. Importantly, obese SK-HGF mice exhibited improved whole-body glucose tolerance independently of changes in body weight or plasma triglyceride levels compared to control mice. This effect on glucose homeostasis was associated with significantly higher (∼80 %) levels of phosphorylated protein kinase B in muscles from SK-HGF mice compared to control mice. In conclusion, muscle expression of HGF counteracts obesity-mediated muscle insulin resistance and improves glucose tolerance in mice.

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Abbreviations

DOX:

Doxycycline

GADPH:

Glyceraldehyde 3-phosphate dehydrogenase

HGF:

Hepatocyte growth factor

IPGTT:

Intraperitoneal glucose tolerance test

IPITT:

Intraperitoneal insulin tolerance test

mHGF:

Mouse HGF

MCK:

Muscle creatine kinase promoter

(PI3K):

Phosphatidylinositol 3-kinase

rtTA:

Reverse tetracycline Transactivator

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Acknowledgments

This study was supported by a grant from ISCIII (CP08/00106), MINECO (SAF2009-11282) and FP7-PEOPLE-2009-RG (PIRG06-GA-2009-25369) to GP; a grant from MINECO (RYC-2011-08101) to IC; and grants from the NIH R-01 (DK067351 and DK077096) to AGO.

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Authors and Affiliations

  1. Research Unit, University Hospital “Puerta del Mar”, Cádiz, Spain

    Viviana Sanchez-Encinales, Irene Cozar-Castellano & Germán Perdomo

  2. Instituto de Genética y Biología Molecular, Universidad de Valladolid-CSIC, Valladolid, Spain

    Irene Cozar-Castellano

  3. Diabetes, Obesity and Metabolism Institute, The Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, Atran 5 Box 1152, 1 Gustave L. Levy Place, New York, NY, 10029, USA

    Adolfo Garcia-Ocaña

  4. School of Environmental Sciences and Biochemistry, University of Castilla-La Mancha, Science-Technology Campus in the Old Weapons Factory, Sabatini Building, Avenue of Charles III, s/n, 45071, Toledo, Spain

    Germán Perdomo

Authors
  1. Viviana Sanchez-Encinales
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  2. Irene Cozar-Castellano
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  3. Adolfo Garcia-Ocaña
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  4. Germán Perdomo
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Corresponding authors

Correspondence to Adolfo Garcia-Ocaña or Germán Perdomo.

Ethics declarations

Experimental procedures were approved by the Animal Care and Use Committee of the University of Cadiz (UCA) in accordance with the European Guidelines for Care and Use of Mammals in Research.

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Sanchez-Encinales, V., Cozar-Castellano, I., Garcia-Ocaña, A. et al. Targeted delivery of HGF to the skeletal muscle improves glucose homeostasis in diet-induced obese mice. J Physiol Biochem 71, 795–805 (2015). https://doi.org/10.1007/s13105-015-0444-6

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  • DOI: https://doi.org/10.1007/s13105-015-0444-6

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