Abstract
Obesity, caused by the dysfunction of white adipose tissue (WAT), is reportedly accompanied by exacerbation of lipolysis. Perilipin 1 (PLIN1), which forms a coat around lipid droplets, interacts with several lipolysis proteins to regulate lipolysis. While it is known that perilipin family proteins are degraded in lysosomes, the underlying molecular mechanisms related to the downregulated expression of PLIN1 in obese WAT remain unknown. Recently, we found that lysosomal dysfunction originating from an abnormality of cathepsin B (CTSB), a lysosomal representative protease, occurs in obese WAT. Therefore, we investigated the effect of CTSB alterations on PLIN1 expression in obese WAT. PLIN1 protein disappeared and CTSB protein appeared in the cytoplasm of adipocytes in the early stage of obese WAT. Overexpression of CTSB reduced PLIN1 protein in 3T3L1 adipocytes, and treatment with a CTSB inhibitor significantly recovered this reduction. In addition, CTSB overexpression induced the dysfunction of lipolysis in 3T3L1 adipocytes. Therefore, we concluded that upregulation of CTSB induced the reduction of PLIN1 protein in obese WAT, resulting in lipolysis dysfunction. This suggests a novel pathology of lipid metabolism involving PLIN1 in adipocytes and that CTSB might be a therapeutic candidate molecule for obese WAT.
Highlights
Obesity, caused by the dysfunction of white adipose tissue (WAT), is reportedly accompanied by exacerbation of lipolysis
WAT, we compared alterations in the expressions of Perilipin 1 (PLIN1) and PLIN2, a perilipin family that is ubiquitously expressed and which participates in lipid droplets (LDs) formation, accompanying high-fat diet (HFD) feeding over a time-course using the normal diet (ND) group as a control
To clarify whether cathepsin B (CTSB) localizes in adipocytes or macrophages, we investigated the localization of CTSB protein in ND and 8HFD mice by immunohistochemistry analysis of WAT sections using anti-CTSB and anti-PLIN1 antibodies combined with anti-F4/80 antibody as a marker for macrophages
Summary
Obesity, caused by the dysfunction of white adipose tissue (WAT), is reportedly accompanied by exacerbation of lipolysis. While it is known that perilipin family proteins are degraded in lysosomes, the underlying molecular mechanisms related to the downregulated expression of PLIN1 in obese WAT remain unknown. We concluded that upregulation of CTSB induced the reduction of PLIN1 protein in obese WAT, resulting in lipolysis dysfunction. This suggests a novel pathology of lipid metabolism involving PLIN1 in adipocytes and that CTSB might be a therapeutic candidate molecule for obese WAT. The Plin[1] gene is epigenetically regulated, and methylation of its promoter was inversely correlated with basal lipolysis in obese women[14] Despite these findings, to date, no consensus has been reached on the mechanisms underlying the obesity-associated downregulation of PLIN1. Here we investigated the involvement of lysosomal alterations in the downregulation of PLIN1 in obese WAT
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