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

Abstract

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.

E3 ubiquitin ligase Wwp1 regulates ciliary dynamics of the Hedgehog receptor Smoothened

“…Wwp1 is a HECT family ligase whose activity has been studied with regard to cancer, where its increased activity is correlated with aggressive tumors ( Chen et al, 2007 ). Knockout mice have short tibias (Mouse Genome Informatics and the International Mouse Phenotyping Consortium) and are obese ( Hoshino et al, 2020 ), two phenotypes that are commonly seen in cilia-defective mice. Wwp1 is reported to catalyze monoubiquitination and the extension of a poly-Ub chain through the rapid addition of two to four K63-linked subunits followed by slower addition of a variety of linkages onto the initial short K63 chain ( French et al, 2017 ).…”

The Identification of Key Genes and Biological Pathways in Polycystic Ovary Syndrome and its Complications by Next Generation Squancing (NGS) and Bioinformatics Analysis

“…GO term and pathway enrichment analysis showed that DEGs were highly enriched in the present investigation, which undoubtedly verifies the reliability of our results. Signaling pathways include cytokine signaling in immune system [ [87], CES1 [88], CYP19A1 [89], PLAC8 [90], CD36 [91], GIPR (gastric inhibitory polypeptide receptor) [92], ARG1 [93], MSR1 [94], DOCK2 [95], S1PR1 [96], OXTR (oxytocin receptor) [97], F11R [98], LEPR (leptin receptor) [99], AR (androgen receptor) [100], DKK3 [101], FOXO1 [102], PIK3CB [103], WWP1 [104], PHIP (pleckstrin homology domain interacting protein) [105], MPZL3 [106], FBXO2 [107], GUCY2C [108], ADRA2A [109], CHRNA5 [110], GLP2R [111], SDC3 [112], NFAT5 [113], PON2 [114], PRNP (prion protein) [115], DGKE (diacylglycerol kinase epsilon) [116], ARHGAP21 [117], COQ2 [118], EPHX2 [119] and FAM3C [120] were observed to be associated with the progression of obesity. Vargas-Alarcón et al [121], Frantz et al [122], Bosè et al [123], Gu et al [124], Liu et al [125], Szirák et al [126], Ye et al [127], Alikhah et al [128], Chen et al [129], Mao et al…”

The regulatory roles of the E3 ubiquitin ligase NEDD4 family in DNA damage response

“…WWP1 is a 922 amino acid protein that contains one C2 domain, four WW domains and one HECT domain (Zhi and Chen, 2012). The C2 domain determines the subcellular localization of the molecule, while the WW domain binds to the proline-rich sequence (PY motif) of the substrate protein (Hoshino et al, 2020). Studies have shown that WWP1 regulates a variety of cellular biological processes such as protein transport and degradation, signal transduction and transcription (Jia et al, 2021).…”