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Sfrp1 is regulated by nutritional signals, genetic obesity and metabolic status in vivo. Sfrp1 mRNA levels, normalized to 18S rRNA, were measured in (a) whole epididymal adipose tissue and (b) mature adipocytes from 8-week-old male C57/Bl6 mice challenged under the following conditions: fed (n=8–9), fasted (24 h) (n=7–8) and refed (24 h) (n=7–8). *P<0.05, **P<0.01, ***P<0.001. (c) Sfrp1 mRNA and (d) Glut4 (Slc2a4) mRNA levels were measured in whole adipose tissue from C57/Bl6 mice fed either chow diet or high-fat diet for 3 days (acute), 4 weeks (short term) or 6 months (long term) post weaning (n=7–8). **P<0.01, ***P<0.001 versus chow-fed mice. (e) Changes in epididymal fat pad weights during HFD feeding relative to chow feeding (f) Expression data from 4-month-old C57/Bl6 mice fed with rodent chow supplemented with or without rosiglitazone (thiazolidinedione) for 3 weeks (n=9–10). *P<0.05 versus untreated mice.
Source publication
The Wnt/β-catenin signaling network offers potential targets to diagnose and uncouple obesity from its metabolic complications. In this study, we investigate the role of the Wnt antagonist, secreted frizzled-related protein 1 (SFRP1), in promoting adipogenesis in vitro and adipose tissue expansion in vivo.
We use a combination of human and murine,...
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... whole white adipose tissue (WAT) and isolated mature adipocytes. In response to 24hr fasting, there was a non- significant trend toward reduced Sfrp1 levels relative to whole adipose tissue collected from fed mice (p=0.07). However, in response to 24hr-refeeding, Sfrp1 mRNA levels were markedly increased beyond the levels found in the fed state (Fig. 4A) suggesting WAT SFRP1 is regulated during changes in nutritional flux. The same profile was observed in mature adipocytes isolated from a separate group of mice subjected to the same manipulation (Fig. ...
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... fed mice (p=0.07). However, in response to 24hr-refeeding, Sfrp1 mRNA levels were markedly increased beyond the levels found in the fed state (Fig. 4A) suggesting WAT SFRP1 is regulated during changes in nutritional flux. The same profile was observed in mature adipocytes isolated from a separate group of mice subjected to the same manipulation (Fig. ...
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... further investigate the physiological regulation of Sfrp1 in the context of sustained positive energy balance, we analysed the expression of Sfrp1 in adipose tissue of mice fed a high fat diet. We observed that following short-term exposure (3 days) to a high fat diet (HFD), Sfrp1 expression was significantly induced (Fig. 4C). Intriguingly, with longer term HFD exposure (i.e. 4 weeks and 6 months), adipose tissue expansion plateaus (Fig 4E) and becomes increasingly dysfunctional as assessed by Glut4 expression (Fig. 4D). During this time, the relative levels of Sfrp1 progressively fall and by 6 months, they drop below the levels observed in lean chow fed ...
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... observed that following short-term exposure (3 days) to a high fat diet (HFD), Sfrp1 expression was significantly induced (Fig. 4C). Intriguingly, with longer term HFD exposure (i.e. 4 weeks and 6 months), adipose tissue expansion plateaus (Fig 4E) and becomes increasingly dysfunctional as assessed by Glut4 expression (Fig. 4D). During this time, the relative levels of Sfrp1 progressively fall and by 6 months, they drop below the levels observed in lean chow fed mice (Fig 4C). ...
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... mice fed a high fat diet. We observed that following short-term exposure (3 days) to a high fat diet (HFD), Sfrp1 expression was significantly induced (Fig. 4C). Intriguingly, with longer term HFD exposure (i.e. 4 weeks and 6 months), adipose tissue expansion plateaus (Fig 4E) and becomes increasingly dysfunctional as assessed by Glut4 expression (Fig. 4D). During this time, the relative levels of Sfrp1 progressively fall and by 6 months, they drop below the levels observed in lean chow fed mice (Fig ...
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... with longer term HFD exposure (i.e. 4 weeks and 6 months), adipose tissue expansion plateaus (Fig 4E) and becomes increasingly dysfunctional as assessed by Glut4 expression (Fig. 4D). During this time, the relative levels of Sfrp1 progressively fall and by 6 months, they drop below the levels observed in lean chow fed mice (Fig 4C). ...
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... (TZD) treatment as a pharmacological approach to stimulate adipogenesis and lipid accumulation in vivo. Mice fed a TZD supplemented diet showed increased expression of adipogenic markers in their adipose tissue such as aP2 (23). More importantly this increase in adipose tissue expandability was associated with significantly increased Sfrp1 levels (Fig. ...
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... rodents could be extrapolated to obesity and metabolic dysregulation in humans. First we profiled SFRP1 expression in adipose tissue in a cohort of 31 non-diabetic white European female subjects across a range of body mass indices (BMI) (Table 1 supplement). Based on our previous observations of murine Sfrp1 expression during diet-induced obesity (Fig. 4C), we postulated that SFRP1 expression in human adipose tissue would also vary in a manner that would be associated with a) the degree of adiposity (i.e. BMI), b) the remaining potential of adipose tissue for further expansion and/or c) the metabolic status (insulin sensitivity). As shown in Figure 5A the profile of SFRP1 expression in ...
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... fact a key difference is that after 6 months of HFD, C57Bl6 mice become severely insulin resistant and have impaired glucose tolerance, while the cross sectional human study recruited individuals with normal glucose tolerance. Given the impaired glucose tolerance of the 6 month HFD-fed mice a better comparison between the human and murine obese groups may be made between the 4 week HFD-fed mice and the obese individuals (Fig 4C vs Fig 5A). Although a complete metabolic profile is not available for this human data set and a small number of female subjects only, were studied, it is clear that this human data can not be used alone to represent the general population. ...
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Citations
... It was reported that the Wnt/β-catenin signaling pathway could drive BMSC toward osteoblasts, but this pathway is inhibited in obesity. Secreted frizzled-related protein 1, an inhibitor of Wnt/β-catenin signaling, has been reported to be increased in mild obesity but falls in morbid obesity, resulting in increased marrow adipose [44]. ...
Periodontal disease is a complex and progressive chronic inflammatory condition that leads to the loss of alveolar bone and teeth. It has been associated with various systemic diseases, including diabetes mellitus and obesity, among others. Some of these conditions are part of the metabolic syndrome cluster, a group of interconnected systemic diseases that significantly raise the risk of cardiovascular diseases, diabetes mellitus, and stroke. The metabolic syndrome cluster encompasses central obesity, dyslipidemia, insulin resistance, and hypertension. In this review, our objective is to investigate the correlation between periodontal disease and the components and outcomes of the metabolic syndrome cluster. By doing so, we aim to gain insights into the fundamental mechanisms that link each systemic condition with the metabolic syndrome. This deeper understanding of the interplay between these conditions and periodontal disease can pave the way for more effective treatments that take into account the broader impact of managing periodontal disease on the comprehensive treatment of systemic diseases, and vice versa.
... SFRP1 was a Wnt antagonist involved in the regulation of adipogenesis and was expressed in both mouse and human mature adipocytes. Further, it has been determined to promote adipogenesis and inhibit the Wnt/β-catenin signaling pathway in vitro [38]. SFRP1 deficiency can increase fat weight and adipocyte size, and was regulated during adipogenesis and obesity itself. ...
MicroRNAs (miRNAs) are essential regulators of numerous biological processes in animals, including adipogenesis. Despite the abundance of miRNAs associated with adipogenesis, their exact mechanisms of action remain largely unknown. Our study highlights the role of bta-miR-484 as a major regulator of adipocyte proliferation, apoptosis, and differentiation. Here, we demonstrated that the expression of bta-miR-484 initially increased during adipogenesis before decreasing. Overexpression of bta-miR-484 in adipocytes ultimately inhibited cell proliferation and differentiation, reduced the number of EdU fluorescence-stained cells, increased the number of G1 phase cells, reduced the number of G2 and S phase cells, and downregulated the expression of proliferation markers (CDK2 and PCNA) and differentiation markers (CEBPA, FABP4, and LPL). Additionally, overexpression of bta-miR-484 promoted the expression of apoptosis-related genes (Caspase 3, Caspase 9, and BAX), and increased the number of apoptotic cells observed via flow cytometry. In contrast, bta-miR-484 inhibition in adipocytes yielded opposite effects to those observed during bta-miR-484 overexpression. Moreover, luciferase reporter assays confirmed SFRP1 as a target gene of bta-miR-484, and revealed that bta-miR-484 downregulates SFRP1 mRNA expression. These findings offer compelling evidence that bta-miR-484 targets SFRP1, inhibits proliferation and differentiation, and promotes apoptosis. Therefore, these results offer novel insights into the bta-miR-484 regulation of adipocyte growth and development.
... Adipogenesis regulates adipose tissue expansion and function [7]. Despite the wellknown role of PTHrP in the differentiation programming of stem cells into different cellular linages, its role in the regulation of adipogenic differentiation by human fat tissuederived stem cells has only been partially elucidated at the gene expression level. ...
Parathyroid-hormone-related protein (PTHrP) is encoded by the PTHLH gene which, via alternative promoter usage and splicing mechanisms, can give rise to at least three isoforms of 139, 141, and 173 amino acids with distinct C-terminals. PTHrP is subjected to different post-translational processing that generates smaller bioactive forms, comprising amino terminus, mid-region (containing a nuclear/nucleolar targeting signal), and carboxy terminus peptides. Both the full-length protein and the discrete peptides are key controllers of viability, proliferation, differentiation, and apoptosis in diverse normal and pathological biological systems via the reprogramming of gene expression and remodulation of PKA or PKC-mediated signalization mechanisms. The aim of this review is to pick up selected studies on PTHrP-associated signatures as revealed by molecular profiling assays, focusing on the available data about exemplary differentiating, differentiated, or nontumoral cell and tissue models. In particular, the data presented relate to adipose, bone, dental, cartilaginous, and skin tissues, as well as intestinal, renal, hepatic, pulmonary, and pancreatic epithelia, with a focus on hepatic fibrosis-, pancreatitis-, and diabetes-related changes as diseased states. When reported, the biochemical and/or physiological aspects associated with the specific molecular modulation of gene expression and signal transduction pathways in the target model systems under examination are also briefly described.
... One is SFRP1, whose expression is altered in obese murine and human scWAT. The SFRP1_/_ mice display reduced fat mass [15]. ...
Background
The fat storage capacity of the adipose tissue prevents ectopic lipid deposition, which is one of the risk factors for metabolic abnormalities in obesity. This capacity depends upon the adipogenic gene expression and blood supply provision for tissue expansion through angiogenesis. Here, we studied hyperplasia/hypertrophy of subcutaneous white adipose tissue (scWAT) concerning adipogenic gene expression, angiogenic status, and metabolic parameters in non-obese and different classes of obese individuals.
Methods
The scWAT samples were collected from 80 individuals. The anthropometric parameters, adipose tissue cell size, serum biochemistry, ER stress-induced XBP1 splicing, PPARγ2, SFRP1, WNT10B, and VEGFA gene expression levels were studied. In addition, the CD31 level was investigated by Western blotting.
Results
The obese individuals had greater waist circumferences and higher serum TG, TC, insulin, and HOMA-IR than the non-obese group. However, the largest adipocyte size, increased TNFα, insulin, and HOMA-IR, and the highest expression level of sXBP1, WNT10B, and VEGFA were observed in Class I obese individuals. It means that inflammation, insulin resistance, and ER stress accompany hypertrophic scWAT adipocytes with limited adipose tissue expansion ability. Furthermore, the Class II + III obese individuals showed high PPARγ2 expression and CD31 levels. There is adipogenesis through hyperplasia in this group. The SFRP1 expression was not significantly different in the studied groups.
Conclusion
The results suggest that the capability of adipogenesis with inadequate angiogenesis is related to the metabolic status, inflammation, and ER function. Therefore, therapeutic strategies that support both angiogenesis and adipogenesis can effectively prevent the complications of obesity.
... Adipogenesis regulates adipose tissue expansion and function [7]. Despite the well-known role of PTHrP in the differentiation programming of stem cells into different cellular linages, its role in the regulation of adipogenic differentiation by human fat tissue-derived stem cells has been only partially elucidated at gene expression level. ...
Parathyroid-hormone-related protein (PTHrP) is encoded by PTHLH gene which, by alternative promoter usage and splicing mechanisms, can give rise to at least three isoforms of 139, 141 and 173 amino acids with distinct C-terminals. PTHrP is subjected to different post-translational processing that generates smaller bioactive forms, comprising amino terminus, midregion (containing a nuclear/nucleolar targeting signal) and carboxy terminus peptides. Both the full-length protein and the discrete peptides are key controllers of viability, proliferation, differentiation and apoptosis in diverse normal and pathological biological systems via the reprogramming of gene expression and remodulation of PKA or PKC-mediated signalization mechanisms. The aim of this review is to pick up selected studies on PTHrP-associated signatures as revealed by molecular profiling assays, focusing on the available data about exemplary differentiating, differentiated or non-tumoral cell and tissue models. In particular, the data presented relate to adipose, bone, dental, cartilaginous and skin tissues, and also intestinal, renal, hepatic, pulmonary and pancreatic epithelia, with a focus on hepatic fibrosis-, pancreatitis- and diabetes-related changes as diseased states. Whether reported, the biochemical and/or physiological aspects associated with the specific molecular modulation of gene expression and signal transduction pathways in the target model systems under examination will be also briefly commented.
... Finally, we found 70 target co-differential genes (Fig. 3d, e), including ADIPOQ and SFRP1, which were related to several pathways such as PPAR signaling (Table S4). SFRP1 gene has been reported that inhibits the Wnt/β-catenin signaling pathway, regulating the adipogenesis both in human and murine [49]. ADIPOQ gene is expressed specifically in adipose tissue [50], which exhibited higher expression in porcine fat tissues including subcutaneous fat and intramuscular fat than LDM in the same population [23]. ...
Background
Intramuscular fat (IMF) content is a critical indicator of pork quality, and abnormal IMF is also relevant to human disease as well as aging. Although N6-methyladenosine (m ⁶ A) RNA modification was recently found to regulate adipogenesis in porcine intramuscular fat, however, the underlying molecular mechanisms was still unclear.
Results
In this work, we collected 20 longissimus dorsi muscle samples with high (average 3.95%) or low IMF content (average 1.22%) from a unique heterogenous swine population for m ⁶ A sequencing (m ⁶ A-seq). We discovered 70 genes show both differential RNA expression and m ⁶ A modification from high and low IMF group, including ADIPOQ and SFRP1 , two hub genes inferred through gene co-expression analysis. Particularly, we observed ADIPOQ , which contains three m ⁶ A modification sites within 3′ untranslated and protein coding region, could promote porcine intramuscular preadipocyte differentiation in an m ⁶ A-dependent manner. Furthermore, we found the YT521‑B homology domain family protein 1 (YTHDF1) could target and promote ADIPOQ mRNA translation.
Conclusions
Our study provided a comprehensive profiling of m ⁶ A methylation in porcine longissimus dorsi muscle and characterized the involvement of m ⁶ A epigenetic modification in the regulation of ADIPOQ mRNA on IMF deposition through an m ⁶ A-YTHDF1-dependent manner.
... Hepsin-deficient mice are resistant to obesity, hyperglycemia, and hyperlipidemia . Another downregulated gene, Sfrp1 is known to express in mature adipocytes and modulates the paracrine regulation of adipogenesis via Wnt/β-catenin signaling (Lagathu et al., 2010). Thbs1 was also downregulated in our dataset, and it has previously been reported to express highly in visceral adipose tissue, loss of which makes mice resistant to diet-induced weight gain (Inoue et al., 2013). ...
Activation of thermogenic adipose tissue depots has been linked to improved metabolism and weight loss. To study the molecular regulation of adipocyte thermogenesis, we performed RNA-Seq on brown adipose tissue (BAT), gonadal white adipose tissue (gWAT), and inguinal white adipose tissue (iWAT) from mice treated with β3-adrenoreceptor agonist CL316,243 (CL). Our analysis revealed diverse transcriptional profile and identified pathways in response to CL treatment. Differentially expressed genes (DEGs) in iWATCL were associated with the upregulation of pathways involved in cellular immune responses and with the upregulation of the browning program. We identified 39 DEGs in beige adipose which included certain heat shock proteins (Hspa1a and Hspa1b), and others suggesting potential associations with browning. Our results highlight transcriptional heterogeneity across adipose tissues and reveal genes specifically regulated in beige adipose, potentially aiding in identifying novel browning pathways.
... Moreover, our transcriptome data suggest a higher predisposition to a fatty phenotype in ACM hiPSC-CMs compared to ASY hiPSC-CMs, already in basal condition. Indeed, the SFRP1 gene was upregulated in ACM hiPSC-CMs compared to ASY hiPSC-CMs and its constitutive expression was described to promote adipogenesis and lipid accumulation [61]. In line with our results, this gene was previously reported to show a higher expression level in the RV of ACM patients compared with RV samples from healthy myocardium [62]. ...
Human induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) are commonly used to model arrhythmogenic cardiomyopathy (ACM), a heritable cardiac disease characterized by severe ventricular arrhythmias, fibrofatty myocardial replacement and progressive ventricular dysfunction. Although ACM is inherited as an autosomal dominant disease, incomplete penetrance and variable expressivity are extremely common, resulting in different clinical manifestations. Here, we propose hiPSC-CMs as a powerful in vitro model to study incomplete penetrance in ACM. Six hiPSC lines were generated from blood samples of three ACM patients carrying a heterozygous deletion of exon 4 in the PKP2 gene, two asymptomatic (ASY) carriers of the same mutation and one healthy control (CTR), all belonging to the same family. Whole exome sequencing was performed in all family members and hiPSC-CMs were examined by ddPCR, western blot, Wes™ immunoassay system, patch clamp, immunofluorescence and RNASeq. Our results show molecular and functional differences between ACM and ASY hiPSC-CMs, including a higher amount of mutated PKP2 mRNA, a lower expression of the connexin-43 protein, a lower overall density of sodium current, a higher intracellular lipid accumulation and sarcomere disorganization in ACM compared to ASY hiPSC-CMs. Differentially expressed genes were also found, supporting a predisposition for a fatty phenotype in ACM hiPSC-CMs. These data indicate that hiPSC-CMs are a suitable model to study incomplete penetrance in ACM.
... One is SFRP1, whose expression is altered in obese murine and human scWAT. The SFRP1_/_ mice display reduced fat mass [15]. Table 1shows the primers used in this study. ...
Background: The fat storage capability of the adipose tissue prevents ectopic lipid deposition, which is one of the risk factors for metabolic abnormalities in obesity. This capability depends on the adipogenic gene expression and blood supply provision for tissue expansion through angiogenesis. Here, we studied hyperplasia/hypertrophy of subcutaneous white adipose tissue (scWAT) concerning adipogenic gene expression, angiogenic status, and metabolic parameters in non-obese, Class I, and Class II+III obese subjects.
Methods: The scWAT samples were collected from 80 subjects. The anthropometric parameters, adipose tissue cell size, serum biochemistry, ER stress induced XBP1 splicing, PPARγ2, SFRP1, WNT10B, and VEGFA gene expression levels were studied. In addition, the CD31 level was investigated by Western blotting.
Results: The obese subjects had greater waist circumferences and higher serum TG, TC, insulin, and HOMA-IR than the non-obese group. The Class I obese group showed the largest adipocyte size, increased TNFα, insulin, HOMA-IR, and sXBP-1, WNT10B, and VEGFAexpression. In contrast, the expression of SFRP1 was not significantly different between all studied groups. The Class II+III obesity group showed high PPARγ2 expression and CD31 levels. Class I obesity, with hypertrophic scWAT adipocytes and limited capability of adipose tissue expansion, showed inflammation, insulin resistance, and ER stress.
Conclusion: The results suggest that the capability of adipogenesis with inadequate angiogenesis is related to metabolic status, inflammation, and ER function. Therefore, therapeutic strategies to simultaneously promote angiogenesis and adipogenesis can effectively prevent obesity complications.
... Adipogenic differentiation of stem cells is a complex process that involves the regulation of many signal transduction pathways, including the Wnt signaling pathway [11,12], the Notch signaling pathway [13,14], the BMP signaling pathway [15,16], and the ERK signaling pathway [17,18]. The ERK cascade usually activates its tyrosine kinase activity by G protein-coupled receptors on the cell membrane and then activates the expression of Ras, Raf, MEK, and ERK in turn. ...
Regenerative medicine and tissue engineering have delivered new healing possibilities to the treatment of soft tissue defects, but the selection of seed cells is critical for treatment. Adipose-derived stem cells have perpetually been a preferred candidate for seed cells due to their wealthy sources, simple access, high plasticity, and powerful value-added capabilities. How to improve the efficiency of adipogenic differentiation is the key to the treatment. Pituitary adenylate cyclase-activating peptide, as a biologically active peptide secreted by the pituitary, is widely involved in regulating the body’s sugar metabolism and lipid metabolism. However, the effects of MPAPO in ADSCs adipogenic differentiation remain unknown. Our results reveal that MPAPO treatment improves the adipogenic differentiation efficiency of ADSCs, including promoting the accumulation of lipid droplets and triglycerides, and the expression of adipocyte protein biomarkers PPARγ and C/EBPa. Additionally, the mechanism studies showed that the effective window of MPAPO-induced adipogenesis was the first 3 days during ADSCs differentiation. MPAPO selectively binds to the PAC1 receptor and promotes adipogenic differentiation of ADSCs by activating the ERK signaling pathway and elevating cell proliferation during postconfluent mitosis stage. Altogether, we demonstrate that MPAPO plays a crucial role in ADSCs adipogenesis, providing experimental basis and data for exploring therapeutic options in tissue defect repair.
Graphical Abstract
