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Diabetologia

, Volume 57, Issue 8, pp 1674–1683 | Cite as

Cathepsin S inhibition lowers blood glucose levels in mice

  • Jean-Charles Lafarge
  • Maria Pini
  • Véronique Pelloux
  • Gabriela Orasanu
  • Guido Hartmann
  • Nicolas Venteclef
  • Thierry Sulpice
  • Guo-Ping Shi
  • Karine Clément
  • Michèle Guerre-Millo
Article

Abstract

Aims/hypothesis

Cathepsin S (CatS) belongs to a family of proteases that have been implicated in several disease processes. We previously identified CatS as a protein that is markedly overexpressed in adipose tissue of obese individuals and downregulated after weight loss and amelioration of glycaemic status induced by gastric bypass surgery. This prompted us to test whether the protease contributes to the pathogenesis of type 2 diabetes using mouse models with CatS inactivation.

Methods

CatS knockout mice and wild-type mice treated with orally active small-molecule CatS inhibitors were fed chow or high-fat diets and explored for change in glycaemic status.

Results

CatS deletion induced a robust reduction in blood glucose, which was preserved in diet-induced obesity and with ageing and was recapitulated with CatS inhibition in obese mice. In vivo testing of glucose tolerance, insulin sensitivity and glycaemic response to gluconeogenic substrates revealed that CatS suppression reduced hepatic glucose production despite there being no improvement in insulin sensitivity. This phenotype relied on downregulation of gluconeogenic gene expression in liver and a lower rate of hepatocellular respiration. Mechanistically, we found that the protein ‘regulated in development and DNA damage response 1’ (REDD1), a factor potentially implicated in reduction of respiratory chain activity, was overexpressed in the liver of mice with CatS deficiency.

Conclusions/interpretation

Our results revealed an unexpected metabolic effect of CatS in promoting pro-diabetic alterations in the liver. CatS inhibitors currently proposed for treatment of autoimmune diseases could help to lower hepatic glucose output in obese individuals at risk for type 2 diabetes.

Keywords

Cathepsin inhibitors Glucose homeostasis Hepatic glucose production Obesity Type 2 diabetes 

Abbreviations

CatS

Cathepsin S

CatS-KO

Cathepsin S knockout

FCCP

Trifluorocarbonylcyanide phenylhydrazone

HFD

High-fat diet

MEF

Mouse embryo fibroblast

OCR

Oxygen consumption rate

REDD1

Regulated in development and DNA damage response 1

RQ

Respiratory quotient

WT

Wild type

Notes

Acknowledgements

The authors thank the following individuals: N. Naour (Haute Autorité de Santé, Paris, France), who contributed to the early phases of this study; S. André (Inserm U872 Team 7, Paris, France) and S. V. Kaveri (Inserm U872 Team 16, Paris, France) for their help with the ovalbumin test and C. Magnan (CNRS EAC 4413, Paris, France), C. Cruciani-Guglielmacci (CNRS EAC 4413, Paris, France), A.-F. Burnol (Inserm U1016, Paris, France), G. Lalmanach (Inserm U1100, Tours, France), F. Andreelli (Inserm U872 Team7, Paris, France), G. Mithieux (Inserm U855, Lyon, France) and A. Mardinoglu (Chalmers University of Technology, Gothenburg, Sweden) for helpful discussions. We also thank S. Vannucci (Weill Cornell Medical College, New York, NY, USA) for commenting on the manuscript. We are grateful to F. Bost (Inserm U1062 Team 7, Nice, France) and L. W. Ellisen (Harvard Medical School, Boston, MA, USA) for giving us the opportunity to use Redd1−/− MEFs and to K. Lolmede (AdipoPhyt, Paris, France) for her crucial help in OxoPlate experiments. We thank J.-F. Bedel (Inserm U872 Team7, Paris, France) and F. Briand (Physiogenex, Toulouse, France) for their expert technical assistance.

Funding

This work was supported by the National Agency of Research (ANR OB-Cat), Inserm Transfert, Region Ile de France/CODDIM (grant to MG-M), Fondation pour la Recherche Medicale/Danone, European Union (FP7, ADAPT) and the National Institutes of Health of the USA (HL60942, HL81090, HL88547 to GPS).

Duality of interest

The authors declare that there is no duality of interest associated with this manuscript.

Contribution statement

MG-M, G-PS, TS and KC contributed to the conception and design of the study. J-CL and MP acquired, analysed and interpreted the data. VP, GO, NV, GH contributed to data acquisition. MG-M, J-CL and MP wrote the manuscript. All authors contributed to the review of the manuscript and approved the final version to be published. MG-M is the guarantor of this work, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of data analysis.

Supplementary material

125_2014_3280_MOESM1_ESM.pdf (167 kb)
ESM Table 1 (PDF 167 kb)
125_2014_3280_MOESM2_ESM.pdf (168 kb)
ESM Table 2 (PDF 168 kb)
125_2014_3280_MOESM3_ESM.pdf (166 kb)
ESM Fig. 1 (PDF 166 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2014

Authors and Affiliations

  • Jean-Charles Lafarge
    • 1
    • 2
    • 3
    • 4
  • Maria Pini
    • 1
    • 2
    • 3
    • 4
  • Véronique Pelloux
    • 1
    • 2
    • 3
    • 4
  • Gabriela Orasanu
    • 5
  • Guido Hartmann
    • 6
  • Nicolas Venteclef
    • 1
    • 2
    • 3
    • 4
  • Thierry Sulpice
    • 7
  • Guo-Ping Shi
    • 5
  • Karine Clément
    • 1
    • 2
    • 3
    • 4
    • 8
    • 9
  • Michèle Guerre-Millo
    • 1
    • 2
    • 3
    • 4
  1. 1.Inserm U872, Centre de Recherche des CordeliersParisFrance
  2. 2.Université Pierre et Marie Curie-Paris 6ParisFrance
  3. 3.Université Paris DescartesParisFrance
  4. 4.Institute of Cardiometabolism and Nutrition (ICAN)Pitié-Salpêtrière HospitalParisFrance
  5. 5.Department of MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBostonUSA
  6. 6.CV and Metabolism DTA, Pharma Research and Early DevelopmentHoffmann La RocheBaselSwitzerland
  7. 7.Physiogenex S.A.S Prologue BiotechLabègeFrance
  8. 8.Nutrition Department, Assistance Publique-Hôpitaux de ParisPitié-Salpêtrière HospitalParisFrance
  9. 9.Center of Research on Human Nutrition Ile de FranceParisFrance

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