Deficiency and inhibition of cathepsin K reduce body weight gain and increase glucose metabolism in mice.
OBJECTIVE
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.


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.


CONCLUSIONS
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.
Yang
Min
M
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Sun
Jiusong
J
Zhang
Tinghu
T
Liu
Jian
J
Zhang
Jie
J
Shi
Michael A
MA
Darakhshan
Froogh
F
Guerre-Millo
Michèle
M
Clement
Karine
K
Gelb
Bruce D
BD
Dolgnov
Gregory
G
Shi
Guo-Ping
GP
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000378:metabolism; D050156:Adipogenesis / Q000235:genetics / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors* / Q000172:deficiency* / Q000235:genetics; D002478:Cells, Cultured; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D015430:Weight Gain / Q000235:genetics / Q000502:physiology*
D001786:Blood Glucose; D015853:Cysteine Proteinase Inhibitors; D005353:Fibronectins; D007328:Insulin; D002403:Cathepsins; C534130:CTSK protein, human; D056657:Cathepsin K; C534132:Ctsk protein, mouse; D005947:Glucose