Leptin Resistance in the Ovary of Obese Mice is Associated with Profound Changes in the Transcriptome of Cumulus Cells

Wołodko, Karolina; Walewska, Edyta; Adamowski, Marek; Castillo-Fernandez, Juan; Kelsey, Gavin; Galvão, António

doi:10.33594/000000228

Cited by 13 publications

(35 citation statements)

References 66 publications

(84 reference statements)

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“…Furthermore, the expression signature of NLRP3 inflammasome components in the ovaries of DIO mice overlapped both tyrosine 985 of leptin receptor (Tyr985ObRb) and Janus kinase 2 (JAK2) phosphorylation profile, with the increase at 4 wk HFD treatment being followed by inhibition at 16 wk HFD and concomitant establishment of leptin resistance (Wołodko et al 2020). Therefore, we analysed the levels of NLRP3 inflammasome components in the ovaries of a previously validated mouse model of pharmacological hyperleptinemia, which presented increased systemic levels of leptin and increased leptin signalling in the ovary without obesity (Wołodko et al 2020), and a genetically obese mouse B6.Cg-Lepob/J (ob/ob), characterised by extreme obesity without leptin. In the pharmacological hyperleptinemic model, ten female B6 8 wk old mice, were treated with leptin intraperitoneally, twice a day for 16 days (16 L), whereas controls were administered saline (16 C) (Wołodko et al 2020).…”

Section: Leptin Signalling In the Ovary Drives Activation Of Nlrp3 Inflammasome During Obesity Progressionmentioning

confidence: 99%

“…Methods followed the previously described (Wołodko et al 2020). The GEO accession number for the dataset Sequencing is under submission.…”

Section: Rna-seq Data From Ccsmentioning

confidence: 99%

“…HFD treatment on NLRP3-induced inflammasome activation in the ovary of mice (Figure 2A). We used the DIO protocol previously validated, in which female mice were fed chow diet (CD) or HFD for 4 or 16 wk (n=8/group) (Wołodko et al 2020). After the DIO protocol, we recorded the average body weight (BW) of 19.7 gram (g) in 4 wk CD group and 24.8 g in 4 wk HFD group, whereas the 16 wk CD presented on average BW of 22.6 g and 16 wk HFD 37.6 g BW (Table 3).…”

Section: Time-course Activation Of Nlrp3-induced Inflammasome In the Ovary Of Dio Micementioning

confidence: 99%

“…Therefore, we analysed the levels of NLRP3 inflammasome components in the ovaries of a previously validated mouse model of pharmacological hyperleptinemia, which presented increased systemic levels of leptin and increased leptin signalling in the ovary without obesity (Wołodko et al 2020), and a genetically obese mouse B6.Cg-Lepob/J (ob/ob), characterised by extreme obesity without leptin. In the pharmacological hyperleptinemic model, ten female B6 8 wk old mice, were treated with leptin intraperitoneally, twice a day for 16 days (16 L), whereas controls were administered saline (16 C) (Wołodko et al 2020). Moreover, ten female ob/ob control (+/?)…”

Section: Leptin Signalling In the Ovary Drives Activation Of Nlrp3 Inflammasome During Obesity Progressionmentioning

confidence: 99%

“…Furthermore, due to lipid accumulation, endoplasmic reticulum (ER) stress, mitochondrial dysfunction and increased ovarian cell apoptosis, these mice displayed anovulation and reduced in vivo fertilization rates (Wu et al 2010), as well as abnormal embryo development (Minge et al 2008). We have recently demonstrated the establishment of leptin resistance in the ovaries of mice treated with HFD (Wołodko et al 2020) was mostly mediated by suppressor of cytokine signalling 3 (SOCS3). Hence, changes in local leptin signalling were shown to contribute to the pathophysiology of ovarian failure in obese females (Wołodko et al 2021).…”

Section: Introductionmentioning

confidence: 99%

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Leptin Signalling in the Ovary of Diet-Induced Obese Mice Regulates Activation of Nod-Like Receptor Protein 3 Inflammasome

Adamowski

Wołodko

Oliveira

et al. 2021

Preprint

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Obesity leads to ovarian dysfunction and the establishment of local leptin resistance. The aim of our study was to characterise levels of Nod-Like Receptor Protein 3 (NLRP3) inflammasome activation during obesity progression in the mouse ovaries and liver and test the putative role of leptin on its regulation. C57BL/6J mice were treated with equine chorionic gonadotropin (eCG) or human chorionic gonadotropin (hCG) for oestrous cycle synchronisation and ovaries collection. In diet-induced obesity (DIO) model, mice were fed chow diet (CD) or high fat diet (HFD) for 4 or 16 weeks (wk), whereas in hyperleptinemic model (LEPT), mice were injected with leptin for 16 days (16L) or saline (16C) and in the genetic obese leptin-deficient ob/ob (+/? and -/-) animals were fed CD for 4wk. Either ovaries and liver were collected, as well as cumulus cells (CCs) after superovulation from DIO and LEPT. In DIO protocol, protein expression of NLRP3 inflammasome components was increased in 4wk HFD, but decreased in 16wk HFD. Moreover LEPT and ob/ob models revealed NLRP3 and IL-1b; upregulation in 16L and downregulation in ob/ob. Transcriptome analysis of CC showed common genes between LEPT and 4wk HFD modulating NLRP3 inflammasome. Moreover analysis in the liver showed upregulation of NLRP3 protein only after 16wk HFD, but also the downregulation of NLRP3 protein in ob/ob-/-. We showed the link between leptin signalling and NLRP3 inflammasome activation in the ovary throughout obesity progression in mice, elucidating the molecular mechanisms underpinning ovarian failure in maternal obesity.

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Section: Leptin Signalling In the Ovary Drives Activation Of Nlrp3 Inflammasome During Obesity Progressionmentioning

confidence: 99%

“…Methods followed the previously described (Wołodko et al 2020). The GEO accession number for the dataset Sequencing is under submission.…”

Section: Rna-seq Data From Ccsmentioning

confidence: 99%

Section: Time-course Activation Of Nlrp3-induced Inflammasome In the Ovary Of Dio Micementioning

confidence: 99%

Section: Leptin Signalling In the Ovary Drives Activation Of Nlrp3 Inflammasome During Obesity Progressionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Leptin Signalling in the Ovary of Diet-Induced Obese Mice Regulates Activation of Nod-Like Receptor Protein 3 Inflammasome

Adamowski

Wołodko

Oliveira

et al. 2021

Preprint

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Fetal growth restriction and placental defects in obese mice are associated with impaired decidualisation: the role of increased leptin signalling modulators SOCS3 and PTPN2

Walewska,

Makowczenko,

Witek

et al. 2024

Cell. Mol. Life Sci.

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Decidualisation of the endometrium is a key event in early pregnancy, which enables embryo implantation. Importantly, the molecular processes impairing decidualisation in obese mothers are yet to be characterised. We hypothesise that impaired decidualisation in obese mice is mediated by the upregulation of leptin modulators, the suppressor of cytokine signalling 3 (SOCS3) and the protein tyrosine phosphatase non-receptor type 2 (PTPN2), together with the disruption of progesterone (P4)-signal transducer and activator of transcription (STAT3) signalling. After feeding mice with chow diet (CD) or high-fat diet (HFD) for 16 weeks, we confirmed the downregulation of P4 and oestradiol (E2) steroid receptors in decidua from embryonic day (E) 6.5 and decreased proliferation of stromal cells from HFD. In vitro decidualised mouse endometrial stromal cells (MESCs) and E6.5 deciduas from the HFD showed decreased expression of decidualisation markers, followed by the upregulation of SOCS3 and PTPN2 and decreased phosphorylation of STAT3. In vivo and in vitro leptin treatment of mice and MESCs mimicked the results observed in the obese model. The downregulation of Socs3 and Ptpn2 after siRNA transfection of MESCs from HFD mice restored the expression level of decidualisation markers. Finally, DIO mice placentas from E18.5 showed decreased labyrinth development and vascularisation and fetal growth restricted embryos. The present study revealed major defects in decidualisation in obese mice, characterised by altered uterine response to E2 and P4 steroid signalling. Importantly, altered hormonal response was associated with increased expression of leptin signalling modulators SOCS3 and PTPN2. Elevated levels of SOCS3 and PTPN2 were shown to molecularly affect decidualisation in obese mice, potentially disrupting the STAT3-PR regulatory molecular hub.

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Macrophage-specific MyD88 deletion and pharmacological inhibition prevents liver damage in non-alcoholic fatty liver disease via reducing inflammatory response

Yang

Luo

Tang

et al. 2022

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Leptin Resistance in the Ovary of Obese Mice is Associated with Profound Changes in the Transcriptome of Cumulus Cells

Abstract: This article is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND). Usage and distribution for commercial purposes as well as any distribution of modified material requires written permission.

Cited by 13 publications

References 66 publications

Leptin Signalling in the Ovary of Diet-Induced Obese Mice Regulates Activation of Nod-Like Receptor Protein 3 Inflammasome

Leptin Signalling in the Ovary of Diet-Induced Obese Mice Regulates Activation of Nod-Like Receptor Protein 3 Inflammasome

Fetal growth restriction and placental defects in obese mice are associated with impaired decidualisation: the role of increased leptin signalling modulators SOCS3 and PTPN2

Macrophage-specific MyD88 deletion and pharmacological inhibition prevents liver damage in non-alcoholic fatty liver disease via reducing inflammatory response

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