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Cathepsin L activity controls adipogenesis and glucose tolerance

Nature Cell Biology volume 9, pages 970–977 (2007)Cite this article

Abstract

Cysteine proteases play an important part in human pathobiology1. This report shows the participation of cathepsin L (CatL) in adipogenesis and glucose intolerance. In vitro studies demonstrate the role of CatL in the degradation of the matrix protein fibronectin, insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF-1R), essential molecules for adipogenesis and glucose metabolism2,3,4,5. CatL inhibition leads to the reduction of human and murine pre-adipocyte adipogenesis or lipid accumulation, protection of fibronectin from degradation, accumulation of IR and IGF-1R β-subunits, and an increase in glucose uptake. CatL-deficient mice are lean and have reduced levels of serum glucose and insulin but increased levels of muscle IR β-subunits, fibronectin and glucose transporter (Glut)-4, although food/water intake and energy expenditure of these mice are no less than their wild-type littermates. Importantly, the pharmacological inhibition of CatL also demonstrates reduced body weight gain and serum insulin levels, and increased glucose tolerance, probably due to increased levels of muscle IR β-subunits, fibronectin and Glut-4 in both diet-induced obese mice and ob/ob mice. Increased levels of CatL in obese and diabetic patients suggest that this protease is a novel target for these metabolic disorders.

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Figure 1: Human pre-adipocyte differentiation.
Figure 2: CatL inhibition affects 3T3-L1 cell adipogenesis and insulin receptor proteolysis.
Figure 3: CatL-deficiency limits weight gain and fat storage.
Figure 4: CatL deficiency increases glucose tolerance.
Figure 5: Pharmacological inhibition of CatL reduces body weight gain and glucose intolerance.

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Acknowledgements

We thank Drs Christoph Peters and Thomas Reinheckel for providing the CatL-deficient mice; Jingming Chen, David Nolan and Corinne Hurtaud for technical assistance; and Karen Williams and Robert Gregory for editorial assistance. This study is partially supported by grants from the Academic Senate Award (G.-P.S.; University of California San Francisco); a private fund from NMPI, LLC (Damariscotta, Maine); and grants from the National Institutes of Health (HL60942 to G.-P.S. and HL073168 to A.D.). Inserm U872 received a grant from the French National Agency of Research (Obcat N° ANR-05-PCOD-026-01) and from FRM (Foundation of Medical Research)/Danone.

Author information

Author notes

  1. Min Yang, Yaou Zhang, Jiehong Pan and Jiusong Sun: Authors contributed equally to this study.

Authors and Affiliations

  1. Cardiovascular Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, 02115, Massachusetts, USA

    Min Yang, Jiusong Sun, Jian Liu, Peter Libby, Galina K. Sukhova & Guo-Ping Shi

  2. Department of Rheumatology, Nanfang Hospital and Nanfang Medical University, Guangzhou, 510515, China

    Min Yang

  3. Department of Medicine, University of California, San Francisco, 94143, California, USA

    Yaou Zhang & Jiehong Pan

  4. Section on Genetics and Epidemiology, Joslin Diabetes Center and Harvard Medical School, Boston, 02215, Massachusetts, USA

    Alessandro Doria

  5. Institute for Health Sciences, Tokushima Bunri University, Tokushima, 770-8514, Japan

    Nobuhiko Katunuma

  6. Department of Medicine, Beth Israel-Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts, 02115, USA

    Odile D. Peroni & Barbara B. Kahn

  7. INSERM, U 872, Nutriomique Team 7, Paris, F-75006, France

    Michèle Guerre-Millo & Karine Clement

  8. Université Pierre et Marie Curie-Paris 6, Centre de Recherche des Cordeliers, UMRS 872, Paris, F-75006, France

    Michèle Guerre-Millo & Karine Clement

  9. Université Paris Descartes, UMRS 872, Paris, F-75006, France

    Michèle Guerre-Millo & Karine Clement

  10. Nutrition Department, AP/HP, Pitié-Salpétrière Hospital, Paris, F-75013, France

    Michèle Guerre-Millo & Karine Clement

Authors
  1. Min Yang
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  14. Guo-Ping Shi
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Contributions

M.Y. maintained the mouse colonies and performed most of the mouse tissue immunoblot analysis and physiology studies. Y.Z. monitored mouse body weight and performed 3T3-L1 cell-related experiments. J.P. performed all human adipocyte-related experiments. J.S. performed experiments related to inhibitor-treatments in mice and cells. J.L. helped human and mouse adipocyte culture. P.L. helped experimental design and manuscript editing. G.K.S. helped adipocyte immunostaining. A.D. provided human serum samples and helped data analysis and presentation. N.K. provided cathepsin L inhibitors. O.D.P. helped experimental design. B.B.K. provided expert suggestions in experimental design and data presentation. M. G-M. and K.C. suggested fibronectin analysis, performed fibronectin experiments in mouse tissues and contributed to the writing of the manuscript. G-P.S. design the experiment, participated in data analysis and presentation, and prepared the manuscript.

Corresponding author

Correspondence to Guo-Ping Shi.

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Supplementary Figure S1 and S2 (PDF 3464 kb)

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Yang, M., Zhang, Y., Pan, J. et al. Cathepsin L activity controls adipogenesis and glucose tolerance. Nat Cell Biol 9, 970–977 (2007). https://doi.org/10.1038/ncb1623

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