RESUMO
White adipose tissue (WAT) is essential for lipid storage and systemic energy homeostasis. Understanding adipocyte formation and stability is key to developing therapies for obesity and metabolic disorders. Through a high-throughput cDNA screen, we identified PATZ1, a POZ/BTB and AT-Hook Containing Zinc Finger 1 protein, as an important adipogenic transcription factor. PATZ1 is expressed in human and mouse adipocyte precursor cells (APCs) and adipocytes. In cellular models, PATZ1 promotes adipogenesis via protein-protein interactions and DNA binding. PATZ1 ablation in mouse adipocytes and APCs leads to a reduced APC pool, decreased fat mass, and hypertrophied adipocytes. ChIP-Seq and RNA-seq analyses show that PATZ1 supports adipogenesis by interacting with transcriptional machinery at the promoter regions of key early adipogenic factors. Mass-spec results show that PATZ1 associates with GTF2I, with GTF2I modulating PATZ1's function during differentiation. These findings underscore PATZ1's regulatory role in adipocyte differentiation and adiposity, offering insights into adipose tissue development.
Assuntos
Adipócitos , Adipogenia , Regiões Promotoras Genéticas , Fatores de Transcrição , Adipogenia/genética , Animais , Camundongos , Humanos , Adipócitos/metabolismo , Adipócitos/citologia , Regiões Promotoras Genéticas/genética , Fatores de Transcrição/metabolismo , Fatores de Transcrição/genética , Diferenciação Celular/genética , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/citologia , Masculino , Células 3T3-L1 , Camundongos Endogâmicos C57BL , Regulação da Expressão GênicaRESUMO
Postprandial IL-1ß surges are predominant in the white adipose tissue (WAT), but its consequences are unknown. Here, we investigate the role of IL-1ß in WAT energy storage and show that adipocyte-specific deletion of IL-1 receptor 1 (IL1R1) has no metabolic consequences, whereas ubiquitous lack of IL1R1 reduces body weight, WAT mass, and adipocyte formation in mice. Among all major WAT-resident cell types, progenitors express the highest IL1R1 levels. In vitro, IL-1ß potently promotes adipogenesis in murine and human adipose-derived stem cells. This effect is exclusive to early-differentiation-stage cells, in which the adipogenic transcription factors C/EBPδ and C/EBPß are rapidly upregulated by IL-1ß and enriched near important adipogenic genes. The pro-adipogenic, but not pro-inflammatory effect of IL-1ß is potentiated by acute treatment and blocked by chronic exposure. Thus, we propose that transient postprandial IL-1ß surges regulate WAT remodeling by promoting adipogenesis, whereas chronically elevated IL-1ß levels in obesity blunts this physiological function.
Assuntos
Adipócitos , Adipogenia , Tecido Adiposo Branco , Proteína beta Intensificadora de Ligação a CCAAT , Interleucina-1beta , Receptores Tipo I de Interleucina-1 , Adipogenia/efeitos dos fármacos , Adipogenia/genética , Animais , Interleucina-1beta/metabolismo , Humanos , Adipócitos/metabolismo , Adipócitos/citologia , Receptores Tipo I de Interleucina-1/metabolismo , Receptores Tipo I de Interleucina-1/genética , Camundongos , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/citologia , Proteína delta de Ligação ao Facilitador CCAAT/metabolismo , Proteína delta de Ligação ao Facilitador CCAAT/genética , Masculino , Camundongos Knockout , Células-Tronco/metabolismo , Células-Tronco/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Diferenciação Celular/efeitos dos fármacosRESUMO
BACKGROUND: Adipose tissue affects not only the meat quality of domestic animals, but also human health. Adipocyte differentiation is regulated by a series of regulatory genes and cyclins. Four and half-LIM protein (FHL2) is positively correlated with the hypertrophy of adipocytes and can cause symptoms such as obesity and diabetes. RESULT: In the transcriptome sequencing analysis of intramuscular adipocytes after three days of differentiation, the differentially expressed gene FHL2 was found. To further explore the biological significance of the differentially expressed gene FHL2, which was downregulated in the mature adipocytes. We revealed the function of FHL2 in adipogenesis through the acquisition and loss of function of FHL2. The results showed that the overexpression of FHL2 significantly increased the expression of adipogenic genes (PPARγ, C/EBPß) and the differentiation of intramuscular and subcutaneous adipocytes. However, silencing FHL2 significantly inhibited adipocyte differentiation. The overexpression of FHL2 increased the number of adipocytes stained with crystal violet and increased the mRNA expression of proliferation marker genes such as CCNE, PCNA, CCND and CDK2. In addition, it significantly increased the rate of EdU positive cells. In terms of apoptosis, overexpression of FHL2 significantly inhibited the expression of P53 and BAX in both intramuscular and subcutaneous adipocytes, which are involved in cell apoptosis. However, overexpression of FHL2 promoted the expression of BCL, but was rescued by the silencing of FHL2. CONCLUSIONS: In summary, FHL2 may be a positive regulator of intramuscular and subcutaneous adipocyte differentiation and proliferation, and acts as a negative regulator of intramuscular and subcutaneous adipocyte apoptosis. These findings provide a theoretical basis for the subsequent elucidation of FHL2 in adipocytes.
Assuntos
Adipócitos , Adipogenia , Cabras , Proteínas com Homeodomínio LIM , Proteínas Musculares , Animais , Cabras/genética , Adipócitos/metabolismo , Adipócitos/citologia , Adipogenia/genética , Proteínas com Homeodomínio LIM/genética , Proteínas com Homeodomínio LIM/metabolismo , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Apoptose/genética , Diferenciação Celular/genética , Proliferação de Células , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Gordura Subcutânea/metabolismo , Gordura Subcutânea/citologia , Perfilação da Expressão GênicaRESUMO
The aim of this study was to elucidate the effect of FAM13A on the differentiation of goat intramuscular precursor adipocytes and its mechanism of action. Here, we cloned the CDS region 2094 bp of the goat FAM13A gene, encoding a total of 697 amino acid residues. Functionally, overexpression of FAM13A inhibited the differentiation of goat intramuscular adipocytes with a concomitant reduction in lipid droplets, whereas interference with FAM13A expression promoted the differentiation of goat intramuscular adipocytes. To further investigate the mechanism of FAM13A inhibiting adipocyte differentiation, 104 differentially expressed genes were screened by RNA-seq, including 95 up-regulated genes and 9 down-regulated genes. KEGG analysis found that the RIG-I receptor signaling pathway, NOD receptor signaling pathway and toll-like receptor signaling pathway may affect adipogenesis. We selected the RIG-I receptor signaling pathway enriched with more differential genes as a potential adipocyte differentiation signaling pathway for verification. Convincingly, the RIG-I like receptor signaling pathway inhibitor (HY-P1934A) blocked this pathway to save the phenotype observed in intramuscular adipocyte with FAM13A overexpression. Finally, the upstream miRNA of FAM13A was predicted, and the targeted inhibition of miR-21-5p on the expression of FAM13A gene was confirmed. In this study, it was found that FAM13A inhibited the differentiation of goat intramuscular adipocytes through the RIG-I receptor signaling pathway, and the upstream miRNA of FAM13A (miR-21-5p) promoted the differentiation of goat intramuscular adipocytes. This work extends the genetic regulatory network of IMF deposits and provides theoretical support for improving human health and meat quality from the perspective of IMF deposits.
Assuntos
Adipócitos , Diferenciação Celular , Cabras , Transdução de Sinais , Animais , Cabras/genética , Cabras/metabolismo , Adipócitos/metabolismo , Adipócitos/citologia , Diferenciação Celular/genética , MicroRNAs/genética , Adipogenia/genética , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismoRESUMO
The distinct anatomic environment in which adipose tissues arise during organogenesis is a principle determinant of their adult expansion capacity. Metabolic disease results from a deficiency in hyperplastic adipose expansion within the dermal/subcutaneous depot; thus, understanding the embryonic origins of dermal adipose is imperative. Using single-cell transcriptomics throughout murine embryogenesis, we characterized cell populations, including Bcl11b + cells, that regulate the development of dermal white adipose tissue (dWAT). We discovered that BCL11b expression modulates the Wnt signaling microenvironment to enable adipogenic differentiation in the dermal compartment. Subcutaneous and visceral adipose arises from a distinct population of Nefl + cells during embryonic organogenesis, whereas Pi16 + /Dpp4 + fibroadipogenic progenitors support obesity-stimulated hypertrophic expansion in the adult. Together, these results highlight the unique regulatory pathways used by anatomically distinct adipose depots, with important implications for human metabolic disease.
Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas Repressoras , Animais , Camundongos , Proteínas Repressoras/genética , Proteínas Repressoras/metabolismo , Regulação da Expressão Gênica no Desenvolvimento/genética , Proteínas Supressoras de Tumor/metabolismo , Proteínas Supressoras de Tumor/genética , Adipogenia/genética , Tecido Adiposo Branco/embriologia , Tecido Adiposo Branco/metabolismo , Via de Sinalização Wnt/genética , Tecido Adiposo/metabolismo , Tecido Adiposo/embriologia , Diferenciação Celular/genética , HumanosRESUMO
BACKGROUND: Osteoporosis (OP) is a systemic bone disease characterized by reduced bone mass and deterioration of bone microstructure, leading to increased bone fragility. Platelets can take up and release cytokines, and a high platelet count has been associated with low bone density. Obesity is strongly associated with OP, and adipose tissue can influence platelet function by secreting adipokines. However, the biological relationship between these factors remains unclear. METHODS: We conducted differential analysis to identify OP platelet-related plasma proteins. And, making comprehensive analysis, including functional enrichment, protein-protein interaction network analysis, and Friends analysis. The key protein, Tetranectin (TNA/CLEC3B), was identified through screening. Then, we analyzed TNA's potential roles in osteogenic and adipogenic differentiation using multiple RNA-seq data sets and validated its effect on osteoclast differentiation and bone resorption function through in vitro experiments. RESULTS: Six OP-platelet-related proteins were identified via differential analysis. Then, we screened the key protein TNA, which was found to be highly expressed in adipose tissue. RNA-seq data suggested that TNA may promote early osteoblast differentiation. In vitro experiments showed that knockdown of TNA expression significantly increased the expression of osteoclast markers, thereby promoting osteoclast differentiation and bone resorption. CONCLUSIONS: We identified TNA as a secreted protein that inhibits osteoclast differentiation and bone resorption. While, it potentially promoted early osteoblast differentiation from bioinformatic results. TNA may play a role in bone metabolism through the adipose-bone axis.
Assuntos
Tecido Adiposo , Biomarcadores , Diferenciação Celular , Lectinas Tipo C , Osteoclastos , Osteoporose , Biomarcadores/metabolismo , Tecido Adiposo/metabolismo , Humanos , Osteoporose/metabolismo , Osteoporose/genética , Diferenciação Celular/fisiologia , Osteoclastos/metabolismo , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Osso e Ossos/metabolismo , Osteogênese/fisiologia , Reabsorção Óssea/metabolismo , Reabsorção Óssea/genética , Osteoblastos/metabolismo , Adipogenia/fisiologia , Adipogenia/genética , Animais , Plaquetas/metabolismoRESUMO
Prostate apoptosis response-4 (Par-4, also known as PAWR) is a ubiquitously expressed tumor suppressor protein that induces apoptosis selectively in cancer cells, while leaving normal cells unaffected. Our previous studies indicated that genetic loss of Par-4 promoted hepatic steatosis, adiposity, and insulin-resistance in chow-fed mice. Moreover, low plasma levels of Par-4 are associated with obesity in human subjects. The mechanisms underlying obesity in rodents and humans are multi-faceted, and those associated with adipogenesis can be functionally resolved in cell cultures. We therefore used pluripotent mouse embryonic fibroblasts (MEFs) or preadipocyte cell lines responsive to adipocyte differentiation cues to determine the potential role of Par-4 in adipocytes. We report that pluripotent MEFs from Par-4-/- mice underwent rapid differentiation to mature adipocytes with an increase in lipid droplet accumulation relative to MEFs from Par-4+/+ mice. Knockdown of Par-4 in 3T3-L1 pre-adipocyte cultures by RNA-interference induced rapid differentiation to mature adipocytes. Interestingly, basal expression of PPARγ, a master regulator of de novo lipid synthesis and adipogenesis, was induced during adipogenesis in the cell lines, and PPARγ induction and adipogenesis caused by Par-4 loss was reversed by replenishment of Par-4. Mechanistically, Par-4 downregulates PPARγ expression by directly binding to its upstream promoter, as judged by chromatin immunoprecipitation and luciferase-reporter studies. Thus, Par-4 transcriptionally suppresses the PPARγ promoter to regulate adipogenesis.
Assuntos
Células 3T3-L1 , Adipócitos , Adipogenia , Proteínas Reguladoras de Apoptose , PPAR gama , Animais , PPAR gama/metabolismo , PPAR gama/genética , Adipogenia/genética , Camundongos , Adipócitos/metabolismo , Adipócitos/citologia , Proteínas Reguladoras de Apoptose/metabolismo , Proteínas Reguladoras de Apoptose/genética , Diferenciação Celular , Humanos , Transcrição Gênica , Regiões Promotoras Genéticas/genética , Fibroblastos/metabolismoRESUMO
Embryonic stem cells are crucial for studying developmental biology due to their self-renewal and pluripotency capabilities. This research investigates the differentiation of mouse ESCs into adipocytes, offering insights into obesity and metabolic disorders. Using a monolayer differentiation approach over 30 days, lipid accumulation and adipogenic markers, such as Cebpb, Pparg, and Fabp4, confirmed successful differentiation. RNA sequencing revealed extensive transcriptional changes, with over 15,000 differentially expressed genes linked to transcription regulation, cell cycle, and DNA repair. This study utilized Robust Rank Aggregation to identify critical regulatory genes like PPARG, CEBPA, and EP300. Network analysis further highlighted Atf5, Ccnd1, and Nr4a1 as potential key players in adipogenesis and its mature state, validated through RT-PCR. While key adipogenic factors showed plateaued expression levels, suggesting early differentiation events, this study underscores the value of ESCs in modeling adipogenesis. These findings contribute to our understanding of adipocyte differentiation and have significant implications for therapeutic strategies targeting metabolic diseases.
Assuntos
Adipócitos , Adipogenia , Diferenciação Celular , Células-Tronco Embrionárias Murinas , Animais , Adipogenia/genética , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Células-Tronco Embrionárias Murinas/citologia , Diferenciação Celular/genética , Adipócitos/metabolismo , Adipócitos/citologia , PPAR gama/metabolismo , PPAR gama/genética , Proteínas Estimuladoras de Ligação a CCAAT/metabolismo , Proteínas Estimuladoras de Ligação a CCAAT/genética , Perfilação da Expressão Gênica , Redes Reguladoras de Genes , Transcrição Gênica , Regulação da Expressão GênicaRESUMO
Cell identities are defined by intrinsic transcriptional networks and spatio-temporal environmental factors. Here, we explored multiple factors that contribute to the identity of adipose stem cells, including anatomic location, microvascular neighborhood, and sex. Our data suggest that adipose stem cells serve a dual role as adipocyte precursors and fibroblast-like cells that shape the adipose tissue's extracellular matrix in an organotypic manner. We further find that adipose stem cells display sexual dimorphism regarding genes involved in estrogen signaling, homeobox transcription factor expression and the renin-angiotensin-aldosterone system. These differences could be attributed to sex hormone effects, developmental origin, or both. Finally, our data demonstrate that adipose stem cells are distinct from mural cells, and that the state of commitment to adipogenic differentiation is linked to their anatomic position in the microvascular niche. Our work supports the importance of sex and microvascular function in adipose tissue physiology.
Assuntos
Adipócitos , Tecido Adiposo , Fibroblastos , Caracteres Sexuais , Células-Tronco , Animais , Feminino , Adipócitos/citologia , Adipócitos/metabolismo , Masculino , Tecido Adiposo/citologia , Tecido Adiposo/metabolismo , Fibroblastos/metabolismo , Fibroblastos/citologia , Células-Tronco/metabolismo , Células-Tronco/citologia , Camundongos , Diferenciação Celular , Adipogenia/genética , Camundongos Endogâmicos C57BL , Matriz Extracelular/metabolismo , HumanosRESUMO
OBJECTIVE: Alternative polyadenylation (APA) is a co-transcriptional process that leads to isoform diversity in the 3' ends of mRNAs. APA is known to occur during differentiation, and its dysregulation is observed in diseases like cancer and autoimmune disorders. It has been previously reported that differentiation of 3T3-L1 cells to adipocytes leads to an overall lengthening of mRNAs, but the proteins involved in this regulation have not been identified. The expression levels of subunits of the cleavage and polyadenylation (C/P) complex can regulate the choice of poly(A) site, which in turn can affect different cellular activities. In this paper, we studied the change in levels of C/P proteins during 3T3-L1 differentiation. RESULTS: We observed that while the RNA expression of these proteins is unchanged during differentiation, the protein levels of some subunits do change, including a decrease in levels of CPSF73, the nuclease that cuts at the poly(A) site. However, overexpression of CPSF73 alone does not affect the efficiency and rate of differentiation.
Assuntos
Células 3T3-L1 , Adipogenia , Diferenciação Celular , Animais , Camundongos , Adipogenia/genética , Poliadenilação , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Adipócitos/metabolismo , Fator de Especificidade de Clivagem e Poliadenilação/metabolismo , Fator de Especificidade de Clivagem e Poliadenilação/genéticaRESUMO
In obesity, the process of adipogenesis largely determines the number of adipocytes in body fat depots. Adipogenesis is regulated by several adipocyte-selective micro-ribonucleic acids (miRNAs) and transcription factors that modulate adipocyte proliferation and differentiation. However, some miRNAs block the expression of master regulators of adipogenesis. Since the specific miRNAs display different expressions during adipogenesis, in mature adipocytes and permanent obesity, their use as biomarkers or therapeutic targets is feasible. Upregulated miRNAs in persistent obesity are downregulated during adipogenesis. Moreover, some of the downregulated miRNAs in obese individuals are upregulated in mature adipocytes. Induction of adipocyte stress and hypertrophy leads to the release of adipocyte-derived exosomes (AdEXs) that contain the cargo molecules, miRNAs. miRNAs are important messengers for intercellular communication involved in metabolic responses and have very specific signatures that direct the metabolic activity of target cells. While each miRNA targets multiple messenger RNAs (mRNAs), which may coordinate or antagonize each other's functions, several miRNAs are dysregulated in other tissues during obesity-related comorbidities. Deletion of the miRNA-processing enzyme DICER in pro-opiomelanocortin-expressing cells results in obesity, which is characterized by hyperphagia, increased adiposity, hyperleptinemia, defective glucose metabolism, and alterations in the pituitary-adrenal axis. In recent years, RNA-based therapeutical approaches have entered clinical trials as novel therapies against overweight and its complications. Development of lipid droplets, macrophage accumulation, macrophage polarization, tumor necrosis factor receptor-associated factor 6 activity, lipolysis, lipotoxicity, and insulin resistance are effectively controlled by miRNAs. Thereby, miRNAs as epigenetic regulators are used to determine the new gene transcripts and therapeutic targets.
Assuntos
Adipogenia , Epigênese Genética , MicroRNAs , Obesidade , Humanos , MicroRNAs/genética , MicroRNAs/metabolismo , Obesidade/genética , Obesidade/metabolismo , Adipogenia/genética , Animais , Adipócitos/metabolismo , Exossomos/metabolismo , Exossomos/genética , Regulação da Expressão GênicaRESUMO
Obesity is a global issue that warrants the identification of more effective therapeutic targets and a better understanding of the pivotal molecular pathogenesis. Annexin A1 (ANXA1) is known to inhibit phospholipase A2, exhibiting anti-inflammatory activity. However, the specific effects of ANXA1 in obesity and the underlying mechanisms of action remain unclear. Our study reveals that ANXA1 levels are elevated in the adipose tissue of individuals with obesity. Whole-body or adipocyte-specific ANXA1 deletion aggravates obesity and metabolic disorders. ANXA1 levels are higher in stromal vascular fractions (SVFs) than in mature adipocytes. Further investigation into the role of ANXA1 in SVFs reveals that ANXA1 overexpression induces lower numbers of mature adipocytes, while ANXA1-knockout SVFs exhibit the opposite effect. This suggests that ANXA1 plays an important role in adipogenesis. Mechanistically, ANXA1 competes with MYC binding protein 2 (MYCBP2) for interaction with PDZ and LIM domain 7 (PDLIM7). This exposes the MYCBP2-binding site, allowing it to bind more readily to the SMAD family member 4 (SMAD4) and promoting its ubiquitination and degradation. SMAD4 degradation downregulates peroxisome proliferator-activated receptor gamma (PPARγ) transcription and reduces adipogenesis. Treatment with Ac2-26, an active peptide derived from ANXA1, inhibits both adipogenesis and obesity through the mechanism. In conclusion, the molecular mechanism of ANXA1 inhibiting adipogenesis was first uncovered in our study, which is a potential target for obesity prevention and treatment.
Assuntos
Adipócitos , Adipogenia , Anexina A1 , Obesidade , PPAR gama , Anexina A1/genética , Anexina A1/metabolismo , Adipogenia/genética , Animais , Obesidade/genética , Obesidade/metabolismo , Obesidade/patologia , Humanos , Camundongos , PPAR gama/genética , PPAR gama/metabolismo , Adipócitos/metabolismo , Adipócitos/patologia , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Células 3T3-L1 , PeptídeosRESUMO
Circular RNAs (circRNAs) in controlling gene expression have been highlighted by increasing evidence, and their dysregulation has been linked to various diseases. However, the limited role of circRNAs in the adipogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) has been explored. High-throughput sequencing of circRNA was carried out on BMSCs and AD induction 7d BMSCs. Then a substantial upregulation of circNDUFA13 was detected among circRNAs in AD induction 7d BMSCs. We found that the adipogenic differentiation of BMSCs was positively linked with circNDUFA13 expression levels. Adipogenesis in BMSCs was effectively inhibited by circNDUFA13 knockdown, whereas overexpression of circNDUFA13 promoted adipogenesis. It was noted that circNDUFA13 regulated the adipogenic differentiation of BMSCs by directly interacting with the signal transducer and activator of transcription 3 (STAT3), which activates CEBPß transcription. The in vitro model also validated the in vivo findings. our results suggest that circNDUFA13 controlled the adipogenic differentiation of BMSCs by targeting STAT3 and CEBPß activation.
Assuntos
Adipogenia , Proteína beta Intensificadora de Ligação a CCAAT , Células-Tronco Mesenquimais , RNA Circular , Fator de Transcrição STAT3 , Animais , Humanos , Adipogenia/genética , Células da Medula Óssea/metabolismo , Células da Medula Óssea/citologia , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Proteína beta Intensificadora de Ligação a CCAAT/genética , Diferenciação Celular , Células Cultivadas , Células-Tronco Mesenquimais/metabolismo , Células-Tronco Mesenquimais/citologia , RNA Circular/genética , RNA Circular/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT3/genéticaRESUMO
Skeletal muscle fibrosis is defined as the excessive accumulation of extracellular matrix (ECM) components and is a hallmark of muscular dystrophies. Fibro-adipogenic progenitors (FAPs) are the main source of ECM, and thus have been strongly implicated in fibrogenesis. In skeletal muscle fibrotic models, including muscular dystrophies, FAPs undergo dysregulations in terms of proliferation, differentiation, and apoptosis, however few studies have explored the impact of FAPs migration. Here, we studied fibroblast and FAPs migration and identified lysophosphatidic acid (LPA), a signaling lipid central to skeletal muscle fibrogenesis, as a significant migration inductor. We identified LPA receptor 1 (LPA1) mediated signaling as crucial for this effect through a mechanism dependent on the Hippo pathway, another pathway implicated in fibrosis across diverse tissues. This cross-talk favors the activation of the Yes-associated protein 1 (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ), leading to increased expression of fibrosis-associated genes. This study reveals the role of YAP in LPA-mediated fibrotic responses as inhibition of YAP transcriptional coactivator activity hinders LPA-induced migration in fibroblasts and FAPs. Moreover, we found that FAPs derived from the mdx4cv mice, a murine model of Duchenne muscular dystrophy, display a heightened migratory phenotype due to enhanced LPA signaling compared to wild-type FAPs. Remarkably, we found that the inhibition of LPA1 or YAP transcriptional coactivator activity in mdx4cv FAPs reverts this phenotype. In summary, the identified LPA-LPA1-YAP pathway emerges as a critical driver of skeletal muscle FAPs migration and provides insights into potential novel targets to mitigate fibrosis in muscular dystrophies.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Movimento Celular , Fibroblastos , Fibrose , Lisofosfolipídeos , Músculo Esquelético , Receptores de Ácidos Lisofosfatídicos , Transdução de Sinais , Proteínas de Sinalização YAP , Lisofosfolipídeos/metabolismo , Animais , Proteínas de Sinalização YAP/metabolismo , Proteínas de Sinalização YAP/genética , Camundongos , Receptores de Ácidos Lisofosfatídicos/metabolismo , Receptores de Ácidos Lisofosfatídicos/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Fibroblastos/metabolismo , Fibroblastos/patologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Humanos , Via de Sinalização Hippo , Camundongos Endogâmicos mdx , Proteínas com Motivo de Ligação a PDZ com Coativador Transcricional/metabolismo , Adipogenia/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/genética , Distrofias Musculares/patologiaRESUMO
Excessive abdominal fat deposition negatively impacts poultry meat production and carcass yield. Identification of novel adipogenesis regulators may help improve production performance declines caused by excessive fat deposition. NUMB Endocytic Adaptor Protein (NUMB) typically functions as a cell fate determinant and plays a significant role in cell development and various diseases. Here, we found that NUMB is abundantly expressed in chicken abdominal fat depots and is induced in cultured adipocytes following adipogenic treatment. The gain- and loss-of-function experiments demonstrated that NUMB promotes the proliferation and G1/S transition of chicken adipocytes, enhances adipocyte differentiation, and increases the expression of PPARγ1 transcript. Through mRNA-seq analysis and molecular experiments, we further confirmed that NUMB inhibits the transcriptional activation of the NOTCH1 pathway and the expression of the downstream transcription factor HES1 by inducing NOTCH1 degradation. Nevertheless, the inhibition of the NOTCH1/HES1 axis alone cannot fully explain NUMB's role in adipogenesis, as NUMB also regulates the expression of multiple adipogenic transcription factors such as E2F1, EGR2, and NR4A3. Our data suggest that NUMB is a potent activator of adipogenesis and enhances our understanding of its regulatory mechanisms in chicken abdominal fat deposition.
Assuntos
Adipócitos , Adipogenia , Galinhas , Animais , Adipogenia/genética , Adipócitos/metabolismo , Adipócitos/citologia , Gordura Abdominal/metabolismo , Diferenciação Celular , Proliferação de Células , Regulação da Expressão Gênica , Transdução de SinaisRESUMO
White adipose tissue (WAT) makes up about 20-25% of total body mass in healthy individuals and is crucial for regulating various metabolic processes, including energy metabolism, endocrine function, immunity, and reproduction. In adipose tissue research, "adipogenesis" is commonly used to refer to the process of adipocyte formation, spanning from stem cell commitment to the development of mature, functional adipocytes. Although, this term should encompass a wide range of processes beyond commitment and differentiation, to also include other stages of adipose tissue development such as hypertrophy, hyperplasia, angiogenesis, macrophage infiltration, polarization, etc. collectively, referred to herein as the adipogenic cycle. The term "differentiation", conversely, should only be used to refer to the process by which committed stem cells progress through distinct phases of subsequent differentiation. Recognizing this distinction is essential for accurately interpreting research findings on the mechanisms and stages of adipose tissue development and function. In this review, we focus on the molecular regulation of white adipose tissue development, from commitment to terminal differentiation, and examine key functional aspects of WAT that are crucial for normal physiology and systemic metabolic homeostasis.
Assuntos
Adipogenia , Tecido Adiposo Branco , Diferenciação Celular , Células-Tronco , Humanos , Tecido Adiposo Branco/metabolismo , Tecido Adiposo Branco/citologia , Animais , Diferenciação Celular/genética , Células-Tronco/metabolismo , Células-Tronco/citologia , Adipogenia/genética , Adipócitos/metabolismo , Adipócitos/citologia , Metabolismo EnergéticoRESUMO
Genome to phenome analysis is necessary in livestock areas because of its various and complex phenotypes. Pork belly is a favorable part of meat worldwide, including East Asia. A previous study has suggested that the three key transcription factors (ZNF444, NFYA and PPARG) affecting pork belly traits include total volume, the volume of total fat and muscle, and component muscles of the corresponding slice. However, other transcription factor genes affecting each slice other than pork belly component traits still needed to be identified. Thus, we aimed to analyze pork belly components at the genome to phenome level for identifying key transcription factor genes and their co-associated networks. The range of node numbers against each component trait via the association weight matrix was from 598 to 3020. Premised on the result, an in silico functional approach was performed. Each co-association network enriched three key transcription factors in adipogenesis and skeletal muscle proliferation, mesoderm development, metabolism, and gene transcription. The three key transcription factors and their related genes may be useful in comprehending their effect of pork belly construction.
Assuntos
Adipogenia , Músculo Esquelético , Fenótipo , Fatores de Transcrição , Animais , Adipogenia/genética , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Músculo Esquelético/metabolismo , Suínos , Carne de Porco/análise , Redes Reguladoras de GenesRESUMO
Senescence of skeletal muscle (SkM) has been a primary contributor to senior weakness and disability in recent years. The gradually declining SkM function associated with senescence has recently been connected to an imbalance between damage and repair. Macrophages (Mac) are involved in SkM aging, and different macrophage subgroups hold different biological functions. Through comprehensive single-cell transcriptomic analysis, we first compared the metabolic pathways and biological functions of different types of cells in young (Y) and old (O) mice SkM. Strikingly, the Mac population in mice SkM was also explored, and we identified a unique Mac subgroup in O SkM characterized by highly expressed SPP1 with strong senescence and adipogenesis features. Further work was carried out on the metabolic and biological processes for these Mac subgroups. Besides, we verified that the proportion of the SPP1+ Mac was increased significantly in the quadriceps tissues of O mice, and the senotherapeutic drug combination dasatinib + quercetin (D + Q) could dramatically reduce its proportion. Our study provides novel insight into the potential role of SPP1+ Mac in SkM, which may serve as a senotherapeutic target in SkM aging.
Assuntos
Envelhecimento , Dasatinibe , Macrófagos , Músculo Esquelético , Análise de Célula Única , Transcriptoma , Animais , Masculino , Camundongos , Adipogenia/genética , Envelhecimento/genética , Senescência Celular/genética , Dasatinibe/farmacologia , Perfilação da Expressão Gênica , Macrófagos/metabolismo , Camundongos Endogâmicos C57BL , Músculo Esquelético/metabolismo , Quercetina/farmacologia , Senoterapia/farmacologiaRESUMO
Single-cell technologies have recently expanded the possibilities for researchers to gain, at an unprecedented resolution level, knowledge about tissue composition, cell complexity, and heterogeneity. Moreover, the integration of data coming from different technologies and sources also offers, for the first time, the possibility to draw a holistic portrait of how cells behave to sustain tissue physiology during the human lifespan and disease. Here, we interrogated and integrated publicly available single-cell RNAseq data to advance the understanding of how macrophages, fibro/adipogenic progenitors, and other cell types establish gene regulatory networks and communicate with each other in the muscle tissue. We identified altered gene signatures and signaling pathways associated with the dystrophic condition, including an enhanced Spp1-Cd44 signaling in dystrophic macrophages. We shed light on the differences among dystrophic muscle aging, considering wild type, mdx, and more severe conditions as in the case of the mdx-2d model. Contextually, we provided details on existing communication relations between muscle niche cell populations, highlighting increased interactions and distinct signaling events that these cells stablish in the dystrophic microenvironment. We believe our findings can help scientists to formulate and test new hypotheses by moving towards a more complete understanding of muscle regeneration and immune system biology.
Assuntos
Macrófagos , Músculo Esquelético , Análise de Célula Única , Animais , Macrófagos/metabolismo , Macrófagos/citologia , Análise de Célula Única/métodos , Músculo Esquelético/metabolismo , Músculo Esquelético/citologia , Músculo Esquelético/patologia , Camundongos , Adipogenia/genética , Células-Tronco/metabolismo , Células-Tronco/citologia , Humanos , Camundongos Endogâmicos mdx , Transdução de Sinais , Redes Reguladoras de GenesRESUMO
It is the purpose of this review to compare differences in postnatal epigenetic programming at the level of DNA and RNA methylation and later obesity risk between infants receiving artificial formula feeding (FF) in contrast to natural breastfeeding (BF). FF bears the risk of aberrant epigenetic programming at the level of DNA methylation and enhances the expression of the RNA demethylase fat mass- and obesity-associated gene (FTO), pointing to further deviations in the RNA methylome. Based on a literature search through Web of Science, Google Scholar, and PubMed databases concerning the dietary and epigenetic factors influencing FTO gene and FTO protein expression and FTO activity, FTO's impact on postnatal adipogenic programming was investigated. Accumulated translational evidence underscores that total protein intake as well as tryptophan, kynurenine, branched-chain amino acids, milk exosomal miRNAs, NADP, and NADPH are crucial regulators modifying FTO gene expression and FTO activity. Increased FTO-mTORC1-S6K1 signaling may epigenetically suppress the WNT/ß-catenin pathway, enhancing adipocyte precursor cell proliferation and adipogenesis. Formula-induced FTO-dependent alterations of the N6-methyladenosine (m6A) RNA methylome may represent novel unfavorable molecular events in the postnatal development of adipogenesis and obesity, necessitating further investigations. BF provides physiological epigenetic DNA and RNA regulation, a compelling reason to rely on BF.