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.
It is widely accepted that caloric restriction (CR) extends lifespan and suppresses various pathophysiological changes. CR suppresses growth hormone/insulin-like growth factor signaling and mechanistic target of rapamycin complex 1 activity, activates sirtuin and enhances mitochondrial redox regulation, but the exact mechanisms are still under debate. In this review, we discuss the mechanisms of CR using evidence from studies of animals that were genetically modified according to recent advances in molecular and genetic technologies, from the viewpoint of the adaptive response hypothesis proposed by Holliday (1989). We then explain the beneficial actions of CR, classified according to whether they operate under feeding or fasting conditions.
White adipose tissue (WAT) is important for maintenance of homeostasis, because it stores energy and secretes adipokines. The WAT of obese people demonstrates mitochondrial dysfunction, accompanied by oxidative stress, which leads to insulin resistance. WW domain‐containing E3 ubiquitin protein ligase 1 (WWP1) is a member of the HECT‐type E3 family of ubiquitin ligases and is associated with several diseases. Recently, we demonstrated that WWP1 is induced specifically in the WAT of obese mice, where it protects against oxidative stress. Here, we investigated the function of WWP1 in WAT of obese mice by analyzing the phenotype of Wwp1 knockout (KO) mice fed a high‐fat diet. The levels of oxidative stress markers were higher in obese WAT from Wwp1 KO mice. Moreover, Wwp1 KO mice had lower activity of citrate synthase, a mitochondrial enzyme. We also measured AKT phosphorylation in obese WAT and found lower levels in Wwp1 KO mice. However, plasma insulin level was low and glucose level was unchanged in obese Wwp1 KO mice. Moreover, both glucose tolerance test and insulin tolerance test were improved in obese Wwp1 KO mice. These findings indicate that WWP1 participates in the antioxidative response and mitochondrial function in WAT, but knockdown of WWP1 improves whole‐body glucose metabolism.
Alterations in adipocyte characteristics are highly implicated in the pathology of obesity. In a recent article, we demonstrated that high-fat diet-induced obesity impairs lysosomal function, thereby suppressing autophagy in mice white adipose tissue. Taurine, an amino acid naturally contained in the normal diet and existing ubiquitously in tissues, has been reported to improve insulin resistance and chronic inflammation in animal models, but underlying mechanisms remain unclear. From these findings, we hypothesized that improvement of obese pathology by taurine may be mediated through recovery of autophagy. In matured 3T3-L1 mouse adipocytes, treatment with taurine-promoted autophagy. Moreover, taurine-induced nuclear translocation of transcription factor EB (TFEB), a master regulator of autophagy- and lysosome-related factors. As this translocation is regulated by several kinase pathways, including extracellular signal-related kinase 1 and 2 (ERK1/2) and mechanistic target of rapamycin protein kinase complex 1 (MTORC1), we examined related signaling elements. Consequently, taurine-reduced phosphorylation levels of ERK1/2 but did not alter the phosphorylation of MTORC1 pathway-associated adenosine monophosphate-activated protein kinase or ribosomal protein S6 kinase. Taken together, these results suggest that taurine may enhance TFEB nuclear translocation through ERK1/2 to accelerate autophagy. The effect discovered in this study may represent a novel mechanism for the improvement of obesity-related pathology by taurine.
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