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PubMed2004

Activity-based probes for protein tyrosine phosphatases.

Protein tyrosine phosphatases (PTPs) are involved in the regulation of many aspects of cellular activity including proliferation, differentiation, metabolism, migration, and survival. Given the large number and complexity of PTPs in cell signaling, new strategies are needed for the integrated analysis of PTPs in the whole proteome. Unfortunately, the activities of many PTPs are tightly regulated by posttranslational mechanisms, limiting the utility of standard genomics and proteomics methods for functional characterization of these enzymes. To facilitate the global analysis of PTPs, we designed and synthesized two activity-based probes that consist of alpha-bromobenzylphosphonate as a PTP-specific trapping device and a linker that connects the trapping device with a biotin tag for visualization and purification. We showed that these probes are active site-directed irreversible inactivators of PTPs and form a covalent adduct with PTPs involving the active site Cys residue. Additionally, we demonstrated that the probes are extremely specific toward PTPs while remaining inert to other proteins, including the whole proteome from Escherichia coli. Consequently, these activity-based PTP probes can be used to profile PTP activity in complex proteomes. The ability to interrogate the entire PTP family on the basis of changes in their activity should greatly accelerate both the assignment of PTP function and the identification of potential therapeutic targets.

Binding Sites↗
PubMed2025

A cross-species multi-omics analyze uncovers conserved molecular mechanisms underlying age-related erectile dysfunction.

BACKGROUND: The urgent need for new treatments is driven by the challenging clinical situation of age-related erectile dysfunction (ARED). AIM: To clarify the conserved molecular mechanisms of ARED across species using multi-omics. METHODS: Rat and mouse models with ARED were developed to facilitate the extraction of mRNA and proteins from the corpus cavernosum for high-throughput sequencing. Bioinformatics techniques were employed to analyze differentially expressed genes and to conduct analyses using the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and protein-protein interaction networks. Verification of the results was carried out using immunofluorescence, hematoxylin-eosin staining, and Masson staining. OUTCOMES: The multi-omics profiles of ARED rats and mice were analyzed and validated across species. RESULTS: In both species, Kyoto Encyclopedia of Genes and Genomes and Gene Ontology analyses of transcriptomic and proteomic data revealed that differentially expressed genes were predominantly enriched in pathways associated with alterations in extracellular matrix composition, downregulation of mitochondrial activity, and disruption of protein homeostasis. Immunofluorescence analysis demonstrated an upregulation of reactive oxygen species expression, coupled with a downregulation of Aldh18a1, collagen, and collagen I expression in the corpus cavernosum of mice and rats with ARED. CLINICAL IMPLICATIONS: To offer a novel approach for enhancing the erectile function in patients with ARED. STRENGTHS AND LIMITATIONS: The primary strength of this study lies in its utilization of cross-species multi-omics sequencing, which has elucidated the conserved molecular mechanisms underlying ARED. However, a significant limitation is the absence of subsequent validation in patients with ARED. CONCLUSIONS: Cross-species multi-omics comparisons present a potentially innovative approach for elucidating the underlying mechanisms and identifying preventive and therapeutic targets for ARED.

aging↗
PubMed2006

Ontogenetic variations in the venom proteome of the Amazonian snake Bothrops atrox.

BACKGROUND: Bothrops atrox is responsible for the majority of snakebite accidents in the Brazilian Amazon region. Previous studies have demonstrated that the biological and pharmacological activities of B. atrox venom alter with the age of the animal. Here, we present a comparative proteome analysis of B. atrox venom collected from specimens of three different stages of maturation: juveniles, sub-adults and adults. RESULTS: Optimized conditions for two-dimensional gel electrophoresis (2-DE) of pooled venom samples were achieved using immobilized pH gradient (IPG) gels of non-linear 3-10 pH range during the isoelectric focusing step and 10-20% gradient polyacrylamide gels in the second dimension. Software-assisted analysis of the 2-DE gels images demonstrated differences in the number and intensity of spots in juvenile, sub-adult and adult venoms. Although peptide mass fingerprinting (PMF) failed to identify even a minor fraction of spots, it allowed us to group spots that displayed similar peptide maps. The spots were subjected to a combination of tandem mass spectrometry and Mascot and MS BLAST database searches that identified several classes of proteins, including metalloproteinases, serine proteinases, lectins, phospholipases A2, L-amino oxidases, nerve growth factors, vascular endothelial growth factors and cysteine-rich secretory proteins. CONCLUSION: The analysis of B. atrox samples from specimens of different ages by 2-DE and mass spectrometry suggested that venom proteome alters upon ontogenetic development. We identified stage specific and differentially expressed polypeptides that may be responsible for the activities of the venom in each developmental stage. The results provide insight into the molecular basis of the relation between symptomatology of snakebite accidents in humans and the venom composition. Our findings underscore the importance of the use of venoms from individual specimen at various stages of maturation for the production of antivenoms.

Journal Article↗
PubMed2000

Proteomics to study genes and genomes.

Proteomics, the large-scale analysis of proteins, will contribute greatly to our understanding of gene function in the post-genomic era. Proteomics can be divided into three main areas: (1) protein micro-characterization for large-scale identification of proteins and their post-translational modifications; (2) 'differential display' proteomics for comparison of protein levels with potential application in a wide range of diseases; and (3) studies of protein-protein interactions using techniques such as mass spectrometry or the yeast two-hybrid system. Because it is often difficult to predict the function of a protein based on homology to other proteins or even their three-dimensional structure, determination of components of a protein complex or of a cellular structure is central in functional analysis. This aspect of proteomic studies is perhaps the area of greatest promise. After the revolution in molecular biology exemplified by the ease of cloning by DNA methods, proteomics will add to our understanding of the biochemistry of proteins, processes and pathways for years to come.

Animals↗
PubMed2025

PhIP-Seq uncovers marked heterogeneity in acute rheumatic fever autoantibodies.

Acute rheumatic fever (ARF) and associated rheumatic heart disease are serious sequelae after infection with group A Streptococcus (Strep A). Autoantibodies are thought to contribute to pathogenesis, with deeper exploration of the autoantibody repertoire needed to improve mechanistic understanding and identify new biomarkers. Phage immunoprecipitation sequencing (PhIP-Seq) with the HuScan library (>250,000 overlapping 90-mer peptides spanning the human proteome) was utilized to analyze autoreactivity in sera from children with ARF, uncomplicated Strep A pharyngitis, and matched healthy controls. A global proteome-wide increase in autoantigen reactivity was observed in ARF, as was marked heterogeneity between patients. Public epitopes, common between individuals with ARF were rare, and comprised less than 1% of all enriched peptides. Differential analysis identified both unknown and previously identified ARF autoantigens, including PPP1R12B, a myosin phosphatase complex regulatory subunit expressed in cardiac muscle, and members of the collagen protein family, respectively. Pathway analysis found antigens from the disease-relevant processes encompassing sarcomere and heart morphogenesis were targeted. In sum, PhIP-Seq has substantially expanded the spectrum of autoantigens in ARF, and reveals the rarity of public epitopes in the disease. It provides further support for the role of epitope spreading in pathogenesis and has identified PPP1R12B as an enriched autoantigen.

Humans↗
PubMed2026

Proteomic analysis of cisplatin-induced spermatogenesis defects in mice.

BACKGROUND: Cisplatin is a crucial chemotherapeutic agent used for treating various cancers; however, its excessive use can cause irreversible damage to the reproductive system, and the protein expression profile of cisplatin-induced testicular injury remains unclear. METHODS: Male C57BL/6 mice were treated with cisplatin at various doses, and testes were collected for histological, immunofluorescence, and proteomic analyses. Germ cell loss and apoptosis were assessed using H&E staining, TUNEL assays, and immunofluorescence for LIN28A, SYCP3, MVH, and CDK1. Label-free quantitative proteomics identified differentially expressed proteins, which were analyzed for functional enrichment and protein-protein interactions. RESULTS: We observed that cisplatin treatment led to smaller testes, reduced sperm count, and a significant decrease in the number of spermatocytes and spermatids in mice. Label-free quantitative proteomic analysis revealed that cisplatin significantly reduced the expression of cyclin-dependent kinase 1 (CDK1), a key spermatogenesis regulator, in the testes. Reduction in CDK1 expression is correlated with spermatogenic arrest, particularly in spermatocytes. CONCLUSION: These findings highlight the critical role of CDK1 in cisplatin-induced spermatogenic dysfunction and provide new insights into fertility preservation strategies for patients with cancer undergoing chemotherapy.

Animals↗
PubMed2001

A proteomic approach to the identification of lung cancer markers.

We have developed a comprehensive approach to the identification of protein markers in lung cancer that includes profiling of tumor tissue and cell lines as well as the analysis of serum for autoantibodies to lung tumor antigens. A large number of proteins that are differentially expressed in the major subtypes of lung cancer have been identified by mass spectrometry. A database of protein expression in lung cancer and other types of cancer has been constructed that integrates two-dimensional gel profiles, mass spectrometry data, quantitative protein data and gene expression data at the RNA level, that serves as a resource for biomarker identification. Analysis of the serological response in lung cancer has led to the identification of novel markers detectable in serum of lung cancer patients at the time of diagnosis. The proteomic approach is likely to yield novel classification schemes and novel markers for early diagnosis of lung cancer.

Biomarkers, Tumor↗
PubMed2002

Hierarchical grid transformation for image warping in the analysis of two-dimensional electrophoresis gels.

Two-dimensional electrophoresis is a widely used method for separating a large number of proteins from complex protein mixtures and for revealing differential patterns of protein expressions. In the computer-assisted proteome research, the comparison of protein separation profiles involves several heuristic steps, ranging from protein spot detection to matching of unknown spots. An important prerequisite for efficient protein spot matching is the image warping step, where the geometric relationship between the gel profiles is modeled on the basis of a given set of known corresponding spots, so-called landmarks, and the locations of unknown spots are predicted using the optimized model. Traditionally, polynomial functions together with least squares optimization has been used, even though this approach is known to be incapable of modeling all the complex distortions inherent in electrophoretic data. To satisfy the need of more flexible gel distortion correction, a hierarchical grid transformation method with stochastic optimization is presented. The method provides an adaptive multiresolution model between the gels, and good correction performance in the practical cross-validation tests suggests that automatic warping of gel images could be based on this approach. We believe that the proposed model also has significance in the ultimate comparison of corresponding protein spots since the matching process should benefit from the closeness of the true spot pairs.

Artifacts↗
PubMed2005

Proteome analysis of cortical neuronal cultures following cycloheximide, heat stress and MK801 preconditioning.

Studying endogenous neuroprotective mechanisms induced by preconditioning may provide drug leads to reduce ischemic neuronal death. In this study, we used 2-DE to examine protein expression following cycloheximide, heat stress, and MK801 preconditioning in rat cortical neuronal cultures. Of 150 differentially expressed protein spots selected for identification the protein or tentative protein(s) were identified in 84 cases, representing 50 different proteins. Different protein spots representing the same protein or closely related protein(s) occurred for 21 of the identified proteins and are likely to represent PTMs or proteolytic fragments of the protein. Six protein spots (actin, elongation factor 1-alpha 1, peptidyl-prolyl cis-transisomerase A, Cu/Zn superoxide dismutase, stathmin, tropomyosin) were differentially expressed in all three preconditioning treatments. Twenty-seven protein spots were differentially expressed in two preconditioning treatments, while 51 spots were differentially expressed in one treatment. Three proteins heterogeneous nuclear ribonucleoproteins A2/B1, mitochondrial stress-70 protein, and tropomyosin were detected in control neuronal cultures, but not following one or more preconditioning treatments, while a posttranslational modified form of the voltage dependent anion channel 1 was only detected following cycloheximide preconditioning. In summary, this study has revealed multiple protein changes potentially involved in neuroprotective and neurodamaging pathways, which require further characterization.

Animals↗
PubMed2025

Integrated proteomic network analysis reveals PTPRC as a central hub protein orchestrating co-expression modules and metabolic dysregulation in renal carcinoma: PTPRC protein molecular action.

The occurrence of renal carcinoma is closely related to a variety of molecular mechanisms and metabolic disorders. PTPRC (protein tyrosine phosphatase receptor C), as an important regulatory protein, was studied to reveal the role of PTPRC in renal carcinoma through comprehensive proteomic network analysis, especially its core position in the coordination of co-expression modules and metabolic disorders. This study was the first to download and process multiple publicly available renal cancer transcriptome data to conduct differential gene expression analysis across datasets. Functional enrichment and disease ontology analysis were performed on the transcriptome of renal cancer, and weighted gene co-expression network (WGCNA) was constructed. The results showed that comprehensive principal component analysis revealed significant differences in the transcriptome of renal cancer, and functional annotation revealed specific pathways associated with renal cancer. WGCNA analysis identified tumor-associated co-expression modules, while multi-omics analysis further identified core regulatory networks including PTPRC. As a central hub protein, PTPRC plays an important coordinating role in the co-expression module and metabolic dysregulation of renal carcinoma. This discovery provides a new perspective for understanding the molecular mechanism of kidney cancer.

Humans↗
PubMed2025

Proteomic analysis reveals distinct cerebrospinal fluid signatures across genetic frontotemporal dementia subtypes.

We used an untargeted mass spectrometric approach, tandem mass tag proteomics, for the identification of proteomic signatures in genetic frontotemporal dementia (FTD). A total of 238 cerebrospinal fluid (CSF) samples from the Genetic FTD Initiative were analyzed, including samples from 107 presymptomatic (44 C9orf72, 38 GRN, and 25 MAPT) and 55 symptomatic (27 C9orf72, 17 GRN, and 11 MAPT) mutation carriers as well as 76 mutation-negative controls ("noncarriers"). We found shared and distinct proteomic alterations in each genetic form of FTD. Among the proteins significantly altered in symptomatic mutation carriers compared with noncarriers, we found that a set of proteins including neuronal pentraxin 2 and fatty acid binding protein 3 changed across all three genetic forms of FTD and patients with Alzheimer's disease from previously published datasets. We observed differential changes in lysosomal proteins among symptomatic mutation carriers with marked abundance decreases in MAPT carriers but not other carriers. Further, we identified mutation-associated proteomic changes already evident in presymptomatic mutation carriers. Weighted gene coexpression network analysis combined with gene ontology annotation revealed clusters of proteins enriched in neurodegeneration and glial responses as well as synapse- or lysosome-related proteins indicating that these are the central biological processes affected in genetic FTD. These clusters correlated with measures of disease severity and were associated with cognitive decline. This study revealed distinct proteomic changes in the CSF of patients with genetic FTD, providing insights into the pathological processes involved in the disease. In addition, we identified proteins that warrant further exploration as diagnostic and prognostic biomarker candidates.

Humans↗
PubMed2025

Exploring proteomic immunoprofiles: common neurological and immunological pathways in multiple sclerosis and type 1 diabetes mellitus.

BACKGROUND: Interest in the study of type 1 diabetes mellitus (T1DM) and multiple sclerosis (MS) has increased because of their significant negative impact on the patient quality of life and the profound implications for the health care system. Although the clinical symptoms of T1DM differ from those of MS, such as pancreatic β-cell failure in T1DM and demyelination in the central nervous system (CNS) in MS, both pathologies are considered as autoimmune-related diseases with shared pathogenic pathways, which include autophagy, inflammation and degeneration, among others. Considering the challenges in obtaining pancreatic β-cells and CNS tissue from patients with T1DM and MS, respectively, it is fundamental to explore alternative methods for evaluating disease status. Proteomic analysis of peripheral blood mononuclear cells (PBMCs) is an ideal approach for identifying novel and potential biomarkers for both autoimmune diseases. METHODS: We conducted a proteomic analysis of PBMCs from patients with T1DM and relapsing remitting Multiple Sclerosis (herein forth MS) patients (n = 9 per condition), using a label-free quantitative proteomics approach. The patients were diagnosed following the American Diabetes Association (ADA) criteria for T1DM and McDonald criteria for MS respectively, and were aged over 18 years and more than 2 years from the onset respectively. RESULTS: A total of 2476 proteins were differentially expressed in PBMCs from patients with T1DM and MS patients compared with those form healthy controls (H). Predictive analysis highlighted 15 common proteins, up- or downregulated in PBMCs from patients with T1DM and MS patients vs. healthy controls, involved in the immune system activity (BTF3, TTR, CD59, CSTB), diseases of the neuronal system (TTR), signal transduction (STMN1, LAMTOR5), metabolism of nucleotides (RPS21), proteins (TTR, ENAM, CD59, RPS21, SRP9) and RNA (SRSF10, RPS21). In addition, this study revealed both shared and distinct molecular patterns between the two conditions. CONCLUSIONS: Compared with H, patients with T1DM and MS presented a specific expression pattern of common proteins has been identified. This pattern underscores the shared mechanisms involved in their immune responses and neurological complications, alongside dysregulation of the autophagy pathway. Notably, CSTB has emerged as a differential biomarker, distinguishing between these two autoimmune diseases.

Humans↗
PubMed1999

The prespore vesicles of Dictyostelium discoideum. Purification, characterization, and developmental regulation.

The coordinate fusion of the prespore vesicles (PSVs) with the plasma membrane at the terminal stage of spore differentiation in Dictyostelium discoideum is an important example of developmentally regulated protein secretion. However, little is known about the composition of the vesicles, the molecular signals regulating secretion, or the mechanics of the membrane fusion. Taking a biochemical approach, we purified PSVs from different developmental stages. These preparations are highly enriched for their specific cargo of spore coat proteins while devoid of markers for other cellular compartments. Electron microscopic observations show that the PSV preparations are homogenous, with the soluble spore coat protein PsB/SP85 distributed throughout the lumen and the acid mucopolysaccharide localized in the central core. During development the PSVs increase in size and density concomitant with an increase in their protein cargo. The PSVs contain approximately 80 proteins, and we have identified a PSV-specific GTP-binding protein that may be involved in regulating vesicle fusion. The PSVs are not clathrin-coated and do not contain the SpiA spore coat protein. The PSV preparations are ideal for a global proteome analysis to identify proteins involved in signal reception, vesicle movement, docking, and fusion in this developmentally regulated organelle.

Animals↗
PubMed2006

Proteomic screening of glucose-responsive and glucose non-responsive MIN-6 beta cells reveals differential expression of proteins involved in protein folding, secretion and oxidative stress.

The glucose-sensitive insulin-secretion (GSIS) phenotype is relatively unstable in long-term culture of beta cells. The purpose of this study was to investigate relative changes in the proteome between glucose-responsive (low passage) and glucose non-responsive (high passage) murine MIN-6 pancreatic beta cells. The 2D-DIGE and subsequent DeCyder analysis detected 3351 protein spots in the pH range of 4-7. Comparing MIN-6(H) to MIN-6(L) and using a threshold of 1.2-fold, the number of proteins with a decrease in expression level was 152 (4.5%), similar was 3140 (93.7%) and increased 59 (1.8%). From the differentially expressed proteins identified in this study, groups of proteins associated with the endoplasmic reticulum (ER) and proteins involved in oxidative stress were found to be significantly decreased in the high-passage (H passage) cells. These proteins included endoplasmic reticulum protein 29 (ERp29); 78-kDa glucose-related protein, (GRP78); 94-kDa glucose-related protein (GRP94); protein disulphide isomerase; carbonyl reductase 3; peroxidoxin 4 and superoxide dismutase 1. These results suggest that non-GSIS MIN-6 cells do not have the same ability/capacity of glucose-responsive MIN-6 cells to successfully fold, modify or secrete proteins and counteract the problems associated with oxidative stress.

Animals↗
PubMed2005

Transcript and proteome analysis reveals reduced expression of calgranulins in head and neck squamous cell carcinoma.

The calcium-binding proteins of the S100 and the annexin protein families have been implicated in a variety of important physiological functions including membrane remodeling, calcium-related intracellular signaling, cytoskeleton dynamics, tissue homeostasis, and formation of the cornified envelope in differentiating keratinocytes. Deregulated expression of members of these families has been reported in different types of neoplasia and other diseases, but the results were not consistent. Here we have applied a combination of cDNA microarrays, quantitative reverse transcriptase-PCR (qRT-PCR) and surface enhanced laser desorption ionisation-time of flight mass spectrometry (SELDI-TOF MS) to study differential expression of these genes in head and neck squamous cell carcinoma (HNSCC). The calgranulins A and B and annexins 1 and 2 were found to be down-regulated in HNSCC, compared with normal mucosa, at both the mRNA and protein level. Upon validation of the differential gene expression by tissue microarray immunohistochemistry, we detected novel expression patterns of calgranulins A and B both in normal mucosa as well as in HNSCC. In contrast to squamous cancer of skin and other cancers in which the calgranulins were found to be up-regulated, most HNSCC showed reduced and widely deranged staining patterns including heterogeneous nuclear, cytoplasmic and membranous staining, and even enhanced staining in the tumor stroma. These observations suggest that the normal function of the calgranulins A and B in mucosa might be different from that in skin.

Calgranulin A↗
PubMed2026

Decoding protein signatures and protein interactions in oral potentially malignant disorders: a systematic review and network analysis.

BACKGROUND: Proteomic profiling offers thorough insights into protein structure and function, as well as it acts as an essential approach for analyzing molecular changes at the tissue level. However, because of the proteome's diversity and dynamic nature, biomarker discovery remains challenging. By combining proteomics with bioinformatics, the level of understanding in relation to molecular interactions and disease processes can be improved. Through an integrative approach, few limitations can be addressed, thereby promoting proteomic profiling for the discovery of new therapeutic targets and novel biomarkers for a variety of disorders. AIM: To identify differentially expressed protein markers and their key molecular pathways associated with Oral Potentially Malignant Disorders. METHODS: Systematic Review was conducted following the PRISMA guidelines and the protocol registered in the International Prospective Register of Systematic Reviews (PROSPERO) with the registration ID number CRD42024557545. A comprehensive literature review was performed using electronic databases, yielding 12,797, studies from which 15 eligible articles were selected. The Newcastle-Ottawa Scale was used to assess the risk of bias. Vote counting was performed to identify proteins reported in more than one study. A bipartite network was constructed using Cytoscape to identify shared and disease-specific protein markers. Lesion-wise protein-protein interaction networks were generated using STRING and analysed in Cytoscape to identify highly interconnected hub proteins, and pathway enrichment analysis for these hubs was performed using Reactome. RESULTS: A total of fifteen studies (Leukoplakia (LK) - n = 1, Proliferative Verrucous Leukoplakia (PVL) - n = 2, Oral Submucous Fibrosis (OSMF) - n = 7, and Oral Lichen Planus (OLP) - n = 5) were included. The Newcastle-Ottawa Scale was used to evaluate methodological quality and the quality of studies included in this systematic review was high for 4 articles and moderate in the remaining 11. The most commonly employed technique was mass spectrometry. A total of 318 candidate proteins (LK - 14, PVL - 82, OSMF - 172, and OLP - 50) were identified across the oral potentially malignant disorders. Key markers identified through vote counting included ERO1A, NUCB1, RHOA, and IL36A for PVL; LUM, KRT1, KRT9, ALB, and VIM for OSMF; and ALB, LYZ, HP, HBB, and AMY1A for OLP. The bipartite network showed that OSMF and OLP shared the highest number of proteins, indicating the strongest overlap among lesions. Network analysis further highlighted distinct hub proteins for each lesion: for LK- AMY1A, AMY1B and APOA1; for PVL- CFL1, RHOA and CDC42; for OSMF- HSP90AA1, ENO1 and SERPINA1; and for OLP- HP, B2M, and ORM1. Lesion-specific pathway enrichment revealed that LK was associated with epithelial differentiation, PVL with oncogenic signaling, OSMF with stress-driven fibrosis, and OLP with immune-mediated inflammation. CONCLUSIONS: Proteomic expression offers insights into disease pathogenesis by identifying important molecular changes across OPMDs. However, the majority of biomarkers are still in the exploratory stage due to the considerable variation in lesion types, sample sources, proteomic techniques, and reporting systems. In order to create reliable and clinically applicable biomarkers, future studies should concentrate on combining multi-omics techniques with large-scale, standardized cohorts.

Humans↗
PubMed2002

Molecular aspects of sex differentiation.

Mammalian sex differentiation involves the action of a cascade of genes. Discovery of the sex-determining region of the Y chromosome (SRY) marked the beginning of the delineation of the genes in the cascade. Studies of the genetics of mammalian sex reversal and the embryogenesis of the mice are essential in this endeavor. A number of genes involved in the pathway have been identified and all except one of these genes have a putative role in male sex differentiation. Besides SRY being the master switch in male sex differentiation the hierarchical relationship of the genes identified are far from being understood. Similarly, our knowledge of the genetic regulation of female sex differentiation is minimal. Differential screening and gene expression profiling bring a new dimension to the pursuit with the identification of a number of genes previously unknown to be involved in sex differentiation. Wider application of functional genomic techniques and introduction of proteomic analyses are expected to shed light to our understanding of this complicated developmental process.

Animals↗
PubMed2003

Mitochondrial biogenesis and remodeling during adipogenesis and in response to the insulin sensitizer rosiglitazone.

White adipose tissue is an important endocrine organ involved in the control of whole-body metabolism, insulin sensitivity, and food intake. To better understand these functions, 3T3-L1 cell differentiation was studied by using combined proteomic and genomic strategies. The proteomics approach developed here exploits velocity gradient centrifugation as an alternative to isoelectric focusing for protein separation in the first dimension. A 20- to 30-fold increase in the concentration of numerous mitochondrial proteins was observed during adipogenesis, as determined by mass spectrometry and database correlation analysis. Light and electron microscopy confirmed a large increase in the number of mitochondrion profiles with differentiation. Furthermore, mRNA profiles obtained by using Affymetrix GeneChips revealed statistically significant increases in the expression of many nucleus-encoded mitochondrial genes during adipogenesis. Qualitative changes in mitochondrial composition also occur during adipose differentiation, as exemplified by increases in expression of proteins involved in fatty acid metabolism and of mitochondrial chaperones. Furthermore, the insulin sensitizer rosiglitazone caused striking changes in mitochondrial shape and expression of selective mitochondrial proteins. Thus, although mitochondrial biogenesis has classically been associated with brown adipocyte differentiation and thermogenesis, our results reveal that mitochondrial biogenesis and remodeling are inherent to adipose differentiation per se and are influenced by the actions of insulin sensitizers.

3T3 Cells↗