Cathepsin S inhibition lowers blood glucose levels in mice
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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.
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.
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.
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.
KeywordsCathepsin inhibitors Glucose homeostasis Hepatic glucose production Obesity Type 2 diabetes
Cathepsin S knockout
Mouse embryo fibroblast
Oxygen consumption rate
Regulated in development and DNA damage response 1
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.
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.
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.
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