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Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores.

ABSTRACT: 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.

SUBMITTER: Funicello M

PROVIDER: S-EPMC1925145 | biostudies-literature | 2007 Aug

REPOSITORIES: biostudies-literature

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Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores.

Funicello Marcella M 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

PloS one 20070801 8

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-/-dis ...[more]

PMID: 17668061

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Project description:Background Obesity, which results from a caloric intake and energy expenditure imbalance, is highly prevalent worldwide. Cathepsin S (CTSS), which is a cysteine protease, is elevated in obesity and may regulate a variety of physiological processes. This study sought to investigate the functional role of CTSS in obesity. Methods Mice were administrated 60 mg/kg of RO5444101 in vivo and fed a high-fat diet (HFD) to induce obesity. The weights of the mice fed a normal-chow diet and a HFD were measured. The expression levels of total triglycerides (TG), total cholesterol (TC), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and monocyte chemoattractant protein-1 (MCP-1) were assessed using appropriate corresponding assay kits. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to estimate the messenger ribonucleic acid (mRNA) expression of CTSS in the serum and the release of M1- and M2-type cytokines, and western blot was used to measure the phosphorylated-nuclear factor kappaB (NF-kappaB) p65 and NF-κB p65 proteins. The mRNA and protein expressions of sterol regulatory element-binding protein 1 (SREBP1), fatty acid synthase (FASN), leptin, and adiponectin were also evaluated by RT-qPCR and western blot. Further, hematoxylin and eosin (H&E), immunohistochemical, and red oil O staining were employed to detect the pathological changes of the epididymal white adipose tissue (eWAT), the macrophage infiltration in the eWAT, and lipid accumulation, respectively. Results We found that CTSS was elevated in the plasma, visceral adipose, and liver tissues of the obese mice. After the administration of 60 mg/kg of RO5444101, the weight of the obese mice decreased, insulin resistance was inhibited, and adipocyte formation was suppressed. The CTSS inhibitor also decreased the level of macrophage infiltration in the eWAT, MCP-1 expression, and the release of M1- and M2-type cytokines in the HFD-induced mice. The CTSS inhibitor appeared to improve the hepatic function parameters and lipid accumulation of the HFD-induced mice. The CTSS inhibitor also appeared to improve the inflammatory damage in the HFD-induced mice. Conclusions CTSS inhibitor helped to protect against HFD-induced adipogenesis, inflammatory infiltration, and hepatic lipid accumulation in obese mice.

Dataset Information

Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores.

Publications

Cathepsin K null mice show reduced adiposity during the rapid accumulation of fat stores.

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