Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in female mice

Patel, Vruti; Bidault, Guillaume; Chambers, Joseph E.; Carobbio, Stefania; Everden, Angharad J. T.; Garcés, Concepción; Dalton, Louise; Gribble, Fiona M.; Vidal-Puig, António; Marciniak, Stefan J.

doi:10.1038/s41598-019-39562-y

Cited by 8 publications

(8 citation statements)

References 51 publications

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“…Dephosphorylation eIF2α by inducible expression of eIF2α phosphatase GADD34 in the liver can improve insulin sensitivity and reduce hepatosteatosis in mice fed a high-fat diet (HFD) 24 , and GADD34-deficient mice become obese with fatty liver by aging and HFD 25 . GADD34-deficient mice also exhibit resistance to diet-induced obesity with reduced food intake 26 , consistent with an effect of hypothalamic eIF2α phosphorylation in regulating feeding behaviors 27 . In addition, it has been reported that protein-tyrosine phosphatase 1B (PTP1B) is involved in ER stress signaling 28 and PTP1B deficiency attenuates protein synthesis in brown adipocytes by increasing PERK phosphorylation 29 .…”

Section: Introductionmentioning

confidence: 54%

Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

et al. 2023

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Brown adipose tissue (BAT) plays a pivotal role in maintaining body temperature and energy homeostasis. BAT dysfunction is associated with impaired metabolic health. Here, we show that Ssu72 phosphatase is essential for mRNA translation of genes required for thermogenesis in BAT. Ssu72 is found to be highly expressed in BAT among adipose tissue depots, and the expression level of Ssu72 is increased upon acute cold exposure. Mice lacking adipocyte Ssu72 exhibit cold intolerance during acute cold exposure. Mechanistically, Ssu72 deficiency alters cytosolic mRNA translation program through hyperphosphorylation of eIF2α and reduces translation of mitochondrial oxidative phosphorylation (OXPHOS) subunits, resulting in mitochondrial dysfunction and defective thermogenesis in BAT. In addition, metabolic dysfunction in Ssu72-deficient BAT returns to almost normal after restoring Ssu72 expression. In summary, our findings demonstrate that cold-responsive Ssu72 phosphatase is involved in cytosolic translation of key thermogenic effectors via dephosphorylation of eIF2α in brown adipocytes, providing insights into metabolic benefits of Ssu72.

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Section: Introductionmentioning

confidence: 54%

Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

et al. 2023

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“…UBAP1 played an important role in NF‐kB signal transduction 30 . It is reported that PPP1R15A inactivation could increase insulin resistance 31 and play a proinflammatory role through endoplasmic reticulum stress 32 . The decrease of MAFF can inhibit the expression of antioxidant genes and increase the apoptosis of β cells induced by oxidative stress, 33 while the overexpression of MAFF can inhibit the transcription of NF‐E2‐related factors, which leads to immune and inflammatory reactions 34 .…”

Section: Discussionmentioning

confidence: 99%

Identification of the shared genes in type 2 diabetes mellitus and osteoarthritis and the role of quercetin

Song,

2024

J Cellular Molecular Medi

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This study investigated the underlying comorbidity mechanism between type 2 diabetes mellitus (T2DM) and osteoarthritis (OA), while also assessing the therapeutic potential of quercetin for early intervention and treatment of these two diseases. The shared genes were obtained through GEO2R, limma and weighted gene co‐expression network analysis (WGCNA), and validated using clinical databases and the area under the curves (ROC). Functional enrichment analysis was conducted to elucidate the underlying mechanisms of comorbidity between T2DM and OA. The infiltration of immune cells was analysed using the CIBERSORT algorithm in conjunction with ESTIMATE algorithm. Subsequently, transcriptional regulation analysis, potential chemical prediction, gene‐disease association, relationships between the shared genes and ferroptosis as well as immunity‐related genes were investigated along with molecular docking. We identified the 12 shared genes (EPHA3, RASIP1, PENK, LRRC17, CEBPB, EFEMP2, UBAP1, PPP1R15A, SPEN, MAFF, GADD45B and KLF4) across the four datasets. Our predictions suggested that targeting these shared genes could potentially serve as therapeutic interventions for both T2DM and OA. Specifically, they are involved in key signalling pathways such as p53, IL‐17, NF‐kB and MAPK signalling pathways. Furthermore, the regulation of ferroptosis and immunity appears to be interconnected in both diseases. Notably, in this context quercetin emerges as a promising drug candidate for treating T2DM and OA by specifically targeting the shared genes. We conducted a bioinformatics analysis to identify potential therapeutic targets, mechanisms and drugs for T2DM and OA, thereby offering novel insights into molecular therapy for these two diseases.

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“…The Ppp1r15a ΔC/ΔC mouse (originally named Ppp1r15atm1Dron ) 16 had been previously backcrossed to achieve 97% C57BL/6 purity as described 5 . Experimental cohorts of male Pppr15a ΔC/ΔC and wild-type mice were generated by het × het breeding pairs unless otherwise stated.…”

Section: Methodsmentioning

confidence: 99%

“…The unfolded protein response (UPR) has been shown to have both protective and pathological roles in development of heart failure 3 4 , and also feeding behaviour 5 6 . The rapid adaptations to diverse stimuli that induce cytosolic and ER stress, such as protein misfolding, loss of metabolites, the production of reactive oxygen species and DNA damage, are in part instigated by the phosphorylation of (eIF2α).…”

Section: Introductionmentioning

confidence: 99%

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice

Takaoka

Tadross

Al-Hadithi

et al. 2022

Preprint

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Heart failure and associated cachexia is an unresolved and important problem. We report a new model of severe heart failure that consistently results in cachexia. Mice lacking the integrated stress response (ISR) induced eIF2α phosphatase, PPP1R15A, exhibit a dilated cardiomyopathy and severe weight loss following irradiation, whilst wildtype mice are unaffected. This is associated with increased expression of Gdf15 in the heart and increased levels of GDF15 in the circulation. We provide evidence that blockade of GDF15 activity prevents cachexia and slows the progression of heart failure. Our data suggests that cardiac stress mediates a GDF15 dependent pathway that drives weight loss and worsens cardiac function. We show relevance of GDF15 to lean mass and protein intake with patients with heart failure. Blockade of GDF15 could constitute a novel therapeutic option to limit cardiac cachexia and improve clinical outcomes in patients with severe systolic heart failure.

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Inactivation of Ppp1r15a minimises weight gain and insulin resistance during caloric excess in female mice

Cited by 8 publications

References 51 publications

Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

Ssu72 phosphatase is essential for thermogenic adaptation by regulating cytosolic translation

Identification of the shared genes in type 2 diabetes mellitus and osteoarthritis and the role of quercetin

GDF15 antagonism limits severe heart failure and prevents cardiac cachexia in mice

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