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.
Keywords: Obesity; adipogenesis; cathepsin S inhibitor (CTSS inhibitor); inflammatory infiltration; lipid accumulation.
2022 Annals of Translational Medicine. All rights reserved.