Identification of WWP1 as an obesity-associated E3 ubiquitin ligase with a protective role against oxidative stress in adipocytes

Kobayashi, Masaki; Hoshino, Shunsuke; Abe, Takuro; Okita, Naoyuki; Tagawa, Ryoma; Nagai, Wataru; Konno, Ryutaro; Suzuki, Yuki; Furuya, Keizo; Ishikawa, Natsumi; Okado, Hitoshi; Oku, Makito; Iwamoto, Machiko; Miura, Yuri; Sudo, Yuka; Higami, Yoshikazu

doi:10.1016/j.bbrc.2018.11.127

Cited by 9 publications

(20 citation statements)

References 32 publications

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“…In our previous study, we identified WWP1 as an obesity-induced factor that positively regulates antioxidative reactions in adipocytes [23]. Consistent with these findings, in the present study, we showed that Wwp1 KO mice exhibit lower obesity-responsive antioxidant capacity.…”

Section: Discussionsupporting

confidence: 92%

“…Wwp1 KO mice showed normal total GSH content when fed the HFD, indicating that WWP1 may contribute to the acute antioxidative response in WAT during the early stages of obesity. This discrepancy is supported by our previously generated proteomic data, which showed that WWP1 positively regulates the expression of antioxidative proteins . We also found that 4‐HNE concentrations were similar in WT and KO mice and in the ND‐ and HFD‐fed groups.…”

Section: Discussionsupporting

confidence: 72%

“…In a recent report, we showed that antioxidant factors (e.g., TRX and PRDX) correlated with WWP1 expression according to proteome analysis in vitro. However, we were unable to identify any significant changes in protein expression from western blot analysis [23]. To our knowledge, the WWP1 substrates that directly contribute to the oxidative stress response have not yet been identified, although TbR1 and Smad2, WWP1 substrates involved in TGFb (transforming growth factor b) signaling, are reported to be associated with the oxidative stress pathway [11,31].…”

Section: Discussionmentioning

confidence: 81%

“…Recently, we found that WWP1 is induced specifically in obese mouse WAT and is protective against oxidative stress in adipocytes [23]. However, we did not provide in vivo evidence for the roles of WWP1 in WAT.…”

mentioning

confidence: 63%

“…3T3‐L1 preadipocytes were purchased from RIKEN Bioresource Center (Ibaraki, Japan). 3T3‐L1/shGFP and 3T3‐L1/shWwp1 preadipocytes were previously established in our laboratory using a retrovirus system .…”

Section: Methodsmentioning

confidence: 99%

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WWP1 knockout in mice exacerbates obesity‐related phenotypes in white adipose tissue but improves whole‐body glucose metabolism

et al. 2020

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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.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 81%

mentioning

confidence: 63%

Section: Methodsmentioning

confidence: 99%

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WWP1 knockout in mice exacerbates obesity‐related phenotypes in white adipose tissue but improves whole‐body glucose metabolism

et al. 2020

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Systemic depletion of WWP1 improves insulin sensitivity and lowers triglyceride content in the liver of obese mice

et al. 2023

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Obesity is a metabolic disorder associated with many diseases. WW domain‐containing E3 ubiquitin protein ligase 1 (WWP1) is a HECT‐type E3 ubiquitin ligase involved in several diseases. Recently, we found that the level of WWP1 is increased in white adipose tissue in a mouse model of obesity and that obese Wwp1 knockout (KO) mice exhibit improved whole‐body glucose metabolism. Here, to determine which insulin‐sensitive tissues contribute to this phenotype, we investigated the levels of several insulin signaling markers in white adipose tissue, liver, and skeletal muscle of Wwp1 KO mice, which were fed a normal or high‐fat diet and transiently treated with insulin. In obese Wwp1 KO mice, phosphorylated Akt levels were increased in the liver but not in white adipose tissue or skeletal muscle. Moreover, the weight and triglyceride content of the liver of obese Wwp1 KO mice were decreased. These results suggest that systemic deletion of WWP1 improves glucose metabolism via enhanced hepatic insulin signaling and suppressed hepatic fat accumulation. In summary, WWP1 participates in obesity‐related metabolic dysfunction and pathologies related to hepatic steatosis via suppressed insulin signaling.

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Murine in vitro cellular models to better understand adipogenesis and its potential applications

et al. 2020

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Identification of WWP1 as an obesity-associated E3 ubiquitin ligase with a protective role against oxidative stress in adipocytes

Cited by 9 publications

References 32 publications

WWP1 knockout in mice exacerbates obesity‐related phenotypes in white adipose tissue but improves whole‐body glucose metabolism

WWP1 knockout in mice exacerbates obesity‐related phenotypes in white adipose tissue but improves whole‐body glucose metabolism

Systemic depletion of WWP1 improves insulin sensitivity and lowers triglyceride content in the liver of obese mice

Murine in vitro cellular models to better understand adipogenesis and its potential applications

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