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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2008;28:2202.)
© 2008 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Deficiency and Inhibition of Cathepsin K Reduce Body Weight Gain and Increase Glucose Metabolism in Mice

Min Yang; Jiusong Sun; Tinghu Zhang; Jian Liu; Jie Zhang; Michael A. Shi; Froogh Darakhshan; Michèle Guerre-Millo; Karine Clement; Bruce D. Gelb; Gregory Dolgnov; Guo-Ping Shi

From the Department of Medicine (M.Y., J.S., J.L., J.Z., M.A.S., G.-P.S.), Brigham and Women’s Hospital, Harvard Medical School, Boston, Mass; Department of Rheumatology (M.Y.), Nanfang Hospital and Southern Medical University, Guangzhou, China; Department of Chemistry (T.Z.), Harvard University, Cambridge, Mass; INSERM, U872 (F.H., M.G.-M., K.C.), Paris, France; Centre de Recherche des Cordeliers (F.H., M.G.-M., K.C.), Université Pierre et Marie Curie-Paris6, Paris, France; Université Paris Descartes (F.H., M.G.-M., K.C.), UMR S 872, Paris, France; the Departments of Pediatrics and Genetics & Genomic Medicine (B.D.G.), Mount Sinai School of Medicine, New York, New York; and the Department of Medicine (G.D.), Stanford University, Stanford, Calif.

Correspondence to Guo-Ping Shi, DSc, Cardiovascular Medicine, Brigham and Women’s Hospital, NRB-7, 77 Avenue Louis Pasteur, Boston, MA 02115 E-mail gshi{at}rics.bwh.harvard.edu

Objectives— Previous studies demonstrated increased levels of cysteine proteases cathepsins in serum and adipose tissues from obese patients. We now provide evidence from a mouse model of obesity to suggest a direct participation of cathepsin K (CatK) in mouse body weight gain and glucose metabolism.

Methods and Results— Using real-time polymerase chain reaction, we detected 12-fold increase in CatK transcripts after adipogenesis of human preadipocytes. Using an immunohistology analysis, we consistently observed high levels of CatK expression in adipose tissues from obese humans and mice. Selective inhibition of CatK activity blocked the lipid accumulation in human and mouse preadipocytes. In mice, CatK deficiency reduced significantly diet-induced body weight gain and serum glucose and insulin levels. Similar results were obtained in diet-induced and genetically created (ob/ob) obese mice after animals were treated with a CatK-selective inhibitor. Mechanistic study demonstrated a role for CatK in degrading fibronectin, a matrix protein that controls adipogenesis. Deficiency or inhibition of CatK leads to fibronectin accumulation in muscle and adipose tissues.

Conclusion— This study demonstrates an essential role of CatK in adipogenesis and mouse body weight gain, possibly via degradation of fibronectin, thus suggesting a novel therapeutic strategy for the control of obesity by regulating CatK activity.

Key Words: cysteine protease • cathepsin K • adipogenesis • obesity • fibronectin