Hepatokine Fetuin B expression is regulated by leptin-STAT3 signalling and associated with leptin in obesity.
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SUBMITTER: Wang D
PROVIDER: S-EPMC9329397 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:ObjectiveDietary obesity is usually linked with hypothalamic leptin resistance, in which the primary impact is an interference in the homeostatic control of body weight and appetite. Notably, proanthocyanidins (PACs), which are the most abundant phenolic compounds present in human diet, modulate adiposity and food intake. The aim of this study was to assess whether PACs could re-establish appropriate leptin signalling in both the hypothalamus and peripheral tissues.DesignMale Wistar rats were fed either a standard chow diet (STD group, n=7) or a cafeteria diet (CD) for 13 weeks. The CD-fed rats were treated with either grape-seed PAC extract (GSPE) at 25?mg? per kg of body weight per day (CD+GSPE group, n=7) or with the vehicle (CD group, n=7) for the last 21 days of the study period. Specific markers for intracellular leptin signalling, inflammation and endoplasmic reticulum stress in the hypothalamus, liver, mesenteric white adipose tissue and skeletal muscle were analysed using immunoblotting and quantitative PCR.ResultsGSPE treatment significantly reduced the food intake but did not reverse the hyperleptinemia and body wt gain assessed. However, the animals treated with GSPE exhibited greater hypothalamic activation of signal transducer and activator of transcription-3, which was associated with a rise in the Pomc mRNA levels compared with the CD group. In addition, this restoration of leptin responsiveness was accompanied by lower local inflammation and increased Sirt1 gene expression. The effects of the GSPE treatment in the peripheral tissues were not as evident as those in the hypothalamus, although the GSPE treatment significantly restored the mRNA levels of Socs3 and Ptp1b in the skeletal muscle.ConclusionsThe use of GSPE reduces hyperphagia and improves the central and peripheral leptin resistance associated with diet-induced obesity. Our results suggest that GSPE could exert these effects partially by increasing Sirt1 expression and preventing hypothalamic inflammation.
| S-EPMC5220160 | biostudies-literature
Project description:Aims/hypothesisNeonatal beta cells carry out a programme of postnatal functional maturation to achieve full glucose responsiveness. A partial loss of the mature phenotype of adult beta cells may contribute to a reduction of functional beta cell mass and accelerate the onset of type 2 diabetes. We previously found that fetuin-A, a hepatokine increasingly secreted by the fatty liver and a determinant of type 2 diabetes, inhibits glucose-stimulated insulin secretion (GSIS) of human islets. Since fetuin-A is a ubiquitous fetal glycoprotein that declines peripartum, we examined here whether fetuin-A interferes with the functional maturity of beta cells.MethodsThe effects of fetuin-A were assessed during in vitro maturation of porcine neonatal islet cell clusters (NICCs) and in adult human islets. Expression alterations were examined via microarray, RNA sequencing and reverse transcription quantitative real-time PCR (qRT-PCR), proteins were analysed by western blotting and immunostaining, and insulin secretion was quantified in static incubations.ResultsNICC maturation was accompanied by the gain of glucose-responsive insulin secretion (twofold stimulation), backed up by mRNA upregulation of genes governing beta cell identity and function, such as NEUROD1, UCN3, ABCC8 and CASR (Log2 fold change [Log2FC] > 1.6). An active TGFβ receptor (TGFBR)-SMAD2/3 pathway facilitates NICC maturation, since the TGFBR inhibitor SB431542 counteracted the upregulation of aforementioned genes and de-repressed ALDOB, a gene disallowed in mature beta cells. In fetuin-A-treated NICCs, upregulation of beta cell markers and the onset of glucose responsiveness were suppressed. Concomitantly, SMAD2/3 phosphorylation was inhibited. Transcriptome analysis confirmed inhibitory effects of fetuin-A and SB431542 on TGFβ-1- and SMAD2/3-regulated transcription. However, contrary to SB431542 and regardless of cMYC upregulation, fetuin-A inhibited beta cell proliferation (0.27 ± 0.08% vs 1.0 ± 0.1% Ki67-positive cells in control NICCs). This effect was sustained by reduced expression (Log2FC ≤ -2.4) of FOXM1, CENPA, CDK1 or TOP2A. In agreement, the number of insulin-positive cells was lower in fetuin-A-treated NICCs than in control NICCs (14.4 ± 1.2% and 22.3 ± 1.1%, respectively). In adult human islets fetuin-A abolished glucose responsiveness, i.e. 1.7- and 1.1-fold change over 2.8 mmol/l glucose in control- and fetuin-A-cultured islets, respectively. In addition, fetuin-A reduced SMAD2/3 phosphorylation and suppressed expression of proliferative genes. Of note, in non-diabetic humans, plasma fetuin-A was negatively correlated (p = 0.013) with islet beta cell area.Conclusions/interpretationOur results suggest that the perinatal decline of fetuin-A relieves TGFBR signalling in islets, a process that facilitates functional maturation of neonatal beta cells. Functional maturity remains revocable in later life, and the occurrence of a metabolically unhealthy milieu, such as liver steatosis and elevated plasma fetuin-A, can impair both function and adaptive proliferation of beta cells.Data availabilityThe RNAseq datasets and computer code produced in this study are available in the Gene Expression Omnibus (GEO): GSE144950; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE144950.
| S-EPMC8099843 | biostudies-literature
Project description:Neonatal beta-cells undergo a maturation process to acquire glucose responsiveness. We hypothesize that in later life, a partial reversal of this maturation might promote beta-cell dysfunction. We previously ascertained that fetuin-A, a fetal glycoprotein downregulated at birth but increasingly secreted when fatty liver develops, inhibits insulin secretion. Here, we evaluate fetuin-A’s impact on beta-cell maturation. In vitro maturation of neonatal porcine islet cell clusters (NICCs) promoted expression of beta-cell markers and TGFBR/SMAD signaling. Fetuin-A reduced both functional and proliferative gene expression and SMAD phosphorylation. Consequently, fetuin-A impaired glucose- and forskolin-dependent secretion, and reduced adaptive beta-cell proliferation. In adult human islets, fetuin-A abolished glucose responsiveness, diminished SMAD phosphorylation and downregulated functional and proliferative genes. Our findings suggest that perinatal decline of fetuin-A relieves TGFBR signaling in neonatal beta-cells, thereby facilitating the onset of postnatal maturation. However, this program remains revocable during adulthood, since fatty liver-derived fetuin-A reverses beta-cells’ maturity, conferring them a neonatal-like phenotype and contributing to their failure.
2020-12-07 | GSE144950 | GEO
Project description:Obesity has been linked to breast cancer progression but the underlying mechanisms remain obscure. Here we report how leptin, an obesity-associated adipokine, regulates a transcriptional pathway to silence a genetic program of epithelial homeostasis in breast cancer stem-like cells (CSC) that promotes malignant progression. Using genome-wide ChIP-seq and RNA expression profiling, we defined a role for activated STAT3 and G9a histone methyltransferase in epigenetic silencing of miR-200c, which promotes the formation of breast CSCs defined by elevated cell surface levels of the leptin receptor (OBR(hi)). Inhibiting the STAT3/G9a pathway restored expression of miR-200c, which in turn reversed the CSC phenotype to a more differentiated epithelial phenotype. In a rat model of breast cancer driven by diet-induced obesity, STAT3 blockade suppressed the CSC-like OBR(hi) population and abrogated tumor progression. Together, our results show how targeting STAT3-G9a signaling regulates CSC plasticity during obesity-related breast cancer progression, suggesting a novel therapeutic paradigm to suppress CSC pools and limit breast malignancy.
| S-EPMC4694051 | biostudies-literature
Project description:ObjectiveAging and chronic glucocorticoid excess share a number of critical features, including the development of central obesity, insulin resistance and osteoporosis. Previous studies have shown that skeletal glucocorticoid signalling increases with aging and that osteoblasts mediate the detrimental skeletal and metabolic effects of chronic glucocorticoid excess. Here, we investigated whether endogenous glucocorticoid action in the skeleton contributes to metabolic dysfunction during normal aging.MethodsMice lacking glucocorticoid signalling in osteoblasts and osteocytes (HSD2OB/OCY-tg mice) and their wild-type littermates were studied until 3, 6, 12 and 18 months of age. Body composition, adipose tissue morphology, skeletal gene expression and glucose/insulin tolerance were assessed at each timepoint. Leptin sensitivity was assessed by arcuate nucleus STAT3 phosphorylation and inhibition of feeding following leptin administration. Tissue-specific glucose uptake and adipose tissue oxygen consumption rate were also measured.ResultsAs they aged, wild-type mice became obese and insulin-resistant. In contrast, HSD2OB/OCY-tg mice remained lean and insulin-sensitive during aging. Obesity in wild-type mice was due to leptin resistance, evidenced by an impaired ability of exogenous leptin to suppress food intake and phosphorylate hypothalamic STAT3, from 6 months of age onwards. In contrast, HSD2OB/OCY-tg mice remained leptin-sensitive throughout the study. Compared to HSD2OB/OCY-tg mice, leptin-resistant wild-type mice displayed attenuated sympathetic outflow, with reduced tyrosine hydroxylase expression in both the hypothalamus and thermogenic adipose tissues. Adipose tissue oxygen consumption rate declined progressively in aging wild-type mice but was maintained in HSD2OB/OCY-tg mice. At 18 months of age, adipose tissue glucose uptake was increased 3.7-fold in HSD2OB/OCY-tg mice, compared to wild-type mice.ConclusionsSkeletal glucocorticoid signalling is critical for the development of leptin resistance, obesity and insulin resistance during aging. These findings underscore the skeleton's importance in the regulation of body weight and implicate osteoblastic/osteocytic glucocorticoid signalling in the aetiology of aging-related obesity and metabolic disease.
| S-EPMC7596342 | biostudies-literature
Project description:The survival rates associated with Wilms tumour (WT) remain dismal despite advancements in detection and treatment strategies. Cancer stem cells (CSCs) are correlated with the initiation, recurrence and metastasis of tumours, but its impact on Wilms cancer stem cell (WCSC) maintenance remains unclear. In this study, CD133+ cells were successfully isolated from a single-cell suspension of the G401 Wilms tumour cell line using magnetic activated cell sorting (MACS). Signal transducers and activators of transcription 3 (STAT3) has been implicated in tumorigenesis, but its contribution to the metastatic progression of WCSCs has not been investigated. Here, we show that STAT3 is overexpressed in WCSCs. Activation of STAT3 in WCSCs initiated a forward feedback loop that was responsible for mediating the aggressive malignant character of Wilms tumour cells in vitro and in vivo. Treatment of CD133+ cells with stattic, a STAT3 inhibitor, also inhibited tumour formation and progression in xenograft animal models in vivo. Collectively, these studies revealed a critical role of STAT3 signalling in WCSC proliferation and motility and a role for CD133 in cancer stem-like cell function, providing evidence for CD133 as a potential therapeutic target in Wilms tumour.
| S-EPMC5929094 | biostudies-literature
Project description:Renal sinus fat (RSF) is a perivascular fat compartment located around renal arteries. In this in vitro and in vivo study we hypothesized that the hepatokine fetuin-A may impair renal function in non alcoholic fatty liver disease (NAFLD) by altering inflammatory signalling in RSF. To study effects of the crosstalk between fetuin-A, RSF and kidney, human renal sinus fat cells (RSFC) were isolated and cocultured with human endothelial cells (EC) or podocytes (PO). RSFC caused downregulation of proinflammatory and upregulation of regenerative factors in cocultured EC and PO, indicating a protective influence of RFSC. However, fetuin-A inverted these benign effects of RSFC from an anti- to a proinflammatory status. RSF was quantified by magnetic resonance imaging and liver fat content by 1H-MR spectroscopy in 449 individuals at risk for type 2 diabetes. Impaired renal function was determined via urinary albumin/creatinine-ratio (uACR). RSF did not correlate with uACR in subjects without NAFLD (n = 212, p = 0.94), but correlated positively in subjects with NAFLD (n = 105, p = 0.0005). Estimated glomerular filtration rate (eGRF) was inversely correlated with RSF, suggesting lower eGFR for subjects with higher RSF (r = 0.24, p < 0.0001). In conclusion, our data suggest that in the presence of NAFLD elevated fetuin-A levels may impair renal function by RSF-induced proinflammatory signalling in glomerular cells.
| S-EPMC5442123 | biostudies-literature
Project description:BackgroundThe fat mass and obesity associated (FTO) gene is related to obesity and type 2 diabetes, but its function is still largely unknown. A link between leptin receptor-signal transducers and activators of transcription 3 (LepR-STAT3) signalling pathway and FTO was recently suggested in the hypothalamus. Because of the presence of FTO in liver and the role of LepR-STAT3 in the control of hepatic metabolism, we investigated both in vitro and in vivo the potential interrelationship between FTO and LepR-STAT3 signalling pathway in liver and the impact of FTO overexpression on leptin action and glucose homeostasis in liver of mice.ResultsWe found that FTO protein expression is regulated by both leptin and IL-6, concomitantly to an induction of STAT3 tyrosine phosphorylation, in leptin receptor (LepRb) expressing HuH7 cells. In addition, FTO overexpression in vitro altered both leptin-induced Y705 and S727 STAT3 phosphorylation, leading to dysregulation of glucose-6-phosphatase (G6P) expression and mitochondrial density, respectively. In vivo, liver specific FTO overexpression in mice induced a reducetion of Y705 phosphorylation of STAT3 in nuclear fraction, associated with reduced SOCS3 and LepR mRNA levels and with an increased G6P expression. Interestingly, FTO overexpression also induced S727 STAT3 phosphorylation in liver mitochondria, resulting in an increase of mitochondria function and density. Altogether, these data indicate that FTO promotes mitochondrial recruitment of STAT3 to the detriment of its nuclear localization, affecting in turn oxidative metabolism and the expression of leptin-targeted genes. Interestingly, these effects were associated in mice with alterations of leptin action and hyperleptinemia, as well as hyperglycemia, hyperinsulinemia and glucose intolerance.ConclusionsAltogether, these data point a novel regulatory loop between FTO and leptin-STAT3 signalling pathways in liver cells, and highlight a new role of FTO in the regulation of hepatic leptin action and glucose metabolism.
| S-EPMC3896784 | biostudies-literature
Project description:BACKGROUND AND PURPOSE: Protection against ischaemia-reperfusion (I/R) injury involves PI3K-Akt and p44/42 MAPK activation. Leptin which regulates appetite and energy balance also promotes myocyte proliferation via PI3K-Akt and p44/42 MAPK activation. We, therefore, hypothesized that leptin may also exhibit cardioprotective activity. EXPERIMENTAL APPROACH: The influence of leptin on I/R injury was examined in perfused hearts from C57Bl/6 J mice that underwent 35 min global ischaemia and 35 min reperfusion, infarct size being assessed by triphenyltetrazolium chloride staining. The concomitant activation of cell-signalling pathways was investigated by Western blotting. The effect of leptin on mitochondrial permeability transition pore (MPTP) opening was studied in rat cardiomyocytes. KEY RESULTS: Leptin (10 nM) administered during reperfusion reduced infarct size significantly. Protection was blocked by either LY294002 or UO126, inhibitors of Akt and p44/42 MAPK, respectively. Western blotting confirmed that leptin stimulated p44/42 MAPK phosphorylation significantly. Akt phosphorylation was also enhanced but did not achieve statistical significance. Additionally, leptin treatment was associated with a significant increase in p38 phosphorylation. By contrast, leptin caused downregulation of phosphorylated and non-phosphorylated STAT3, and of total AMP-activated kinase. Cardiomyocytes responded to leptin with delayed opening of the MPTP and delayed time until contracture. CONCLUSIONS AND IMPLICATIONS: Our data indicate for the first time that the adipocytokine, leptin, has direct cardioprotective properties which may involve the PI3-Akt and p44/42 MAPK pathways.
| S-EPMC1629412 | biostudies-other
Project description:Prostate cancer (PCa) is the most prevalent cancer in men. Hyperactive STAT3 is thought to be oncogenic in PCa. However, targeting of the IL-6/STAT3 axis in PCa patients has failed to provide therapeutic benefit. Here we show that genetic inactivation of Stat3 or IL-6 signalling in a Pten-deficient PCa mouse model accelerates cancer progression leading to metastasis. Mechanistically, we identify p19(ARF) as a direct Stat3 target. Loss of Stat3 signalling disrupts the ARF-Mdm2-p53 tumour suppressor axis bypassing senescence. Strikingly, we also identify STAT3 and CDKN2A mutations in primary human PCa. STAT3 and CDKN2A deletions co-occurred with high frequency in PCa metastases. In accordance, loss of STAT3 and p14(ARF) expression in patient tumours correlates with increased risk of disease recurrence and metastatic PCa. Thus, STAT3 and ARF may be prognostic markers to stratify high from low risk PCa patients. Our findings challenge the current discussion on therapeutic benefit or risk of IL-6/STAT3 inhibition.
| S-EPMC4525303 | biostudies-literature