Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores.
Growing evidences indicate that proteases are implicated in adipogenesis and in the onset of obesity. We previously reported that the cysteine protease cathepsin K (ctsk) is overexpressed in the white adipose tissue (WAT) of obese individuals. We herein characterized the WAT and the metabolic phenotype of ctsk deficient animals (ctsk-/-). When the growth rate of ctsk-/- was compared to that of the wild type animals (WT), we could establish a time window (5-8 weeks of age) within which ctsk-/-display significantly lower body weight and WAT size as compared to WT. Such a difference was not observable in older mice. Upon treatment with high fat diet (HFD) for 12 weeks ctsk-/- gained significantly less weight than WT and showed reduced brown adipose tissue, liver mass and a lower percentage of body fat. Plasma triglycerides, cholesterol and leptin were significantly lower in HFD-fed-ctsk-/- as compared to HFD-fed WT animals. Adipocyte lipolysis rates were increased in both young and HFD-fed-ctsk-/-, as compared to WT. Carnitine palmitoyl transferase-1 activity, was higher in mitochondria isolated from the WAT of HFD treated ctsk-/- as compared to WT. Together, these data indicate that ctsk ablation in mice results in reduced body fat content under conditions requiring a rapid accumulation of fat stores. This observation could be partly explained by an increased release and/or utilization of FFA and by an augmented ratio of lipolysis/lipogenesis. These results also demonstrate that under a HFD, ctsk deficiency confers a partial resistance to the development of dyslipidemia.
Funicello
Marcella
M
Dulbecco Telethon Institute at Department of Endocrinology and Metabolism, University Hospital of Pisa, Pisa, Italy.
Novelli
Michela
M
Ragni
Maurizio
M
Vottari
Teresa
T
Cocuzza
Cesare
C
Soriano-Lopez
Joaquin
J
Chiellini
Chiara
C
Boschi
Federico
F
Marzola
Pasquina
P
Masiello
Pellegrino
P
Saftig
Paul
P
Santini
Ferruccio
F
St-Jacques
Rene
R
Desmarais
Sylvie
S
Morin
Nicolas
N
Mancini
Joseph
J
Percival
M David
MD
Pinchera
Aldo
A
Maffei
Margherita
M
D050156:Adipogenesis / Q000502:physiology; D052436:Adipose Tissue, White / Q000166:cytology / Q000378:metabolism*; D050154:Adiposity / Q000502:physiology*; D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D056657:Cathepsin K / Q000235:genetics / Q000378:metabolism; D004041:Dietary Fats / Q000378:metabolism; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D004734:Energy Metabolism; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D005951:Glucose Tolerance Test; D008066:Lipolysis; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000378:metabolism
D004041:Dietary Fats; D002334:Carnitine O-Palmitoyltransferase; D056657:Cathepsin K