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PloS One 2022We previously showed that some adipogenic transcription factors such as CEBPB and PPARG directly and indirectly regulate autophagy gene expression in adipogenesis. The...
We previously showed that some adipogenic transcription factors such as CEBPB and PPARG directly and indirectly regulate autophagy gene expression in adipogenesis. The order and effect of these events are undetermined. In this study, we modeled the gene expression, DNA-binding of transcriptional regulators, and histone modifications during adipocyte differentiation and evaluated the effect of the regulators on gene expression in terms of direction and magnitude. Then, we identified the overlap of the transcription factors and co-factors binding sites and targets. Finally, we built a chromatin state model based on the histone marks and studied their relation to the factors' binding. Adipogenic factors differentially regulated autophagy genes as part of the differentiation program. Co-regulators associated with specific transcription factors and preceded them to the regulatory regions. Transcription factors differed in the binding time and location, and their effect on expression was either localized or long-lasting. Adipogenic factors disproportionately targeted genes coding for autophagy-specific transcription factors. In sum, a hierarchical arrangement between adipogenic transcription factors and co-factors drives the regulation of autophagy during adipocyte differentiation.
Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Autophagy; Cell Differentiation; Cell Line; Computational Biology; Gene Expression Regulation; Mice
PubMed: 35081114
DOI: 10.1371/journal.pone.0250865 -
International Journal of Molecular... May 2021Bisphenol A (BPA) is an endocrine-disrupting chemical used in the production of plastics, and is linked to developmental, reproductive, and metabolic disorders including...
Bisphenol A (BPA) is an endocrine-disrupting chemical used in the production of plastics, and is linked to developmental, reproductive, and metabolic disorders including obesity. Manufacturers have begun using 'BPA-free' alternatives instead of BPA in many consumer products. However, these alternatives have had much less testing and oversight, yet they are already being mass-produced and used across industries from plastics to food-contact coatings. Here, we used human female adipose-derived stem cells (hASCs), a type of adult mesenchymal stem cell, to compare the effects of BPA and BPA alternatives on adipogenesis or fat cell development . We focused on two commonly used BPA replacements, bisphenol AF (BPAF) and tetramethyl bisphenol F (TMBPF; monomer of the new valPure V70 food-contact coating). Human ASCs were differentiated into adipocytes using chemically defined media in the presence of control differentiation media with and without 17β-estradiol (E2; 10 μM), or with increasing doses of BPA (0, 0.1 and 1 μM), BPAF (0, 0.1, 1 and 10 nM), or TMBPF (0, 0.01 and 0.1 μM). After differentiation, the cells were stained and imaged to visualize and quantify the accumulation of lipid vacuoles and number of developing fat cells. Treated cells were also examined for cell viability and apoptosis (programmed cell death) using the respective cellular assays. Similar to E2, BPA at 0.1 μM and BPAF at 0.1 nM, significantly increased adipogenesis and lipid production by 20% compared to control differentiated cells (based on total lipid vacuole number to cell number ratios), whereas higher levels of BPA and BPAF significantly decreased adipogenesis ( < 0.005). All tested doses of TMBPF significantly reduced adipogenesis and lipid production by 30-40%, likely at least partially through toxic effects on stem cells, as viable cell numbers decreased and apoptosis levels increased throughout differentiation. These findings indicate that low, environmentally-relevant doses of BPA, BPAF, and TMBPF have significant effects on fat cell development and lipid accumulation, with TMBPF having non-estrogenic, anti-adipogenic effects. These and other recent results may provide a potential cellular mechanism between exposure to bisphenols and human obesity, and underscore the likely impact of these chemicals on fat development in vivo.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Adult Stem Cells; Apoptosis; Benzhydryl Compounds; Cell Differentiation; Cell Survival; Endocrine Disruptors; Estradiol; Female; Humans; Mesenchymal Stem Cells; Obesity; Phenols; Stem Cells
PubMed: 34069744
DOI: 10.3390/ijms22105363 -
Nature Communications Jun 2023Successful muscle regeneration relies on the interplay of multiple cell populations. However, the signals required for this coordinated intercellular crosstalk remain...
Successful muscle regeneration relies on the interplay of multiple cell populations. However, the signals required for this coordinated intercellular crosstalk remain largely unknown. Here, we describe how the Hedgehog (Hh) signaling pathway controls the fate of fibro/adipogenic progenitors (FAPs), the cellular origin of intramuscular fat (IMAT) and fibrotic scar tissue. Using conditional mutagenesis and pharmacological Hh modulators in vivo and in vitro, we identify DHH as the key ligand that acts as a potent adipogenic brake by preventing the adipogenic differentiation of FAPs. Hh signaling also impacts muscle regeneration, albeit indirectly through induction of myogenic factors in FAPs. Our results also indicate that ectopic and sustained Hh activation forces FAPs to adopt a fibrogenic fate resulting in widespread fibrosis. In this work, we reveal crucial post-developmental functions of Hh signaling in balancing tissue regeneration and fatty fibrosis. Moreover, they provide the exciting possibility that mis-regulation of the Hh pathway with age and disease could be a major driver of pathological IMAT formation.
Topics: Adipogenesis; Cell Differentiation; Fibrosis; Hedgehog Proteins; Ligands; Muscle, Skeletal; Signal Transduction; Animals
PubMed: 37355632
DOI: 10.1038/s41467-023-39506-1 -
ELife Jul 2020Complex interaction between genetics, epigenetics, environment, and nutrition affect the physiological activities of adipose tissues and their dysfunctions, which lead... (Review)
Review
Complex interaction between genetics, epigenetics, environment, and nutrition affect the physiological activities of adipose tissues and their dysfunctions, which lead to several metabolic diseases including obesity or type 2 diabetes. Here, adipogenesis appears to be a process characterized by an intricate network that involves many transcription factors and long noncoding RNAs (lncRNAs) that regulate gene expression. LncRNAs are being investigated to determine their contribution to adipose tissue development and function. LncRNAs possess multiple cellular functions, and they regulate chromatin remodeling, along with transcriptional and post-transcriptional events; in this way, they affect gene expression. New investigations have demonstrated the pivotal role of these molecules in modulating white and brown/beige adipogenic tissue development and activity. This review aims to provide an update on the role of lncRNAs in adipogenesis and adipose tissue function to promote identification of new drug targets for treating obesity and related metabolic diseases.
Topics: Adipogenesis; Adipose Tissue; Adipose Tissue, Brown; Adipose Tissue, White; Chromatin Assembly and Disassembly; Gene Regulatory Networks; Humans; RNA, Long Noncoding; Transcription Factors
PubMed: 32730204
DOI: 10.7554/eLife.59053 -
Journal of Cellular Physiology Apr 2014G-protein coupled receptors (GPCRs) are a large family of proteins that coordinate extracellular signals to produce physiologic outcomes. Adenosine receptors (AR) are... (Review)
Review
G-protein coupled receptors (GPCRs) are a large family of proteins that coordinate extracellular signals to produce physiologic outcomes. Adenosine receptors (AR) are one class of GPCRs that have been shown to regulate functions as diverse as inflammation, blood flow, and cellular differentiation. Adenosine signals through four GPCRs that either inhibit (A1AR and A3AR) or activate (A2aAR and A2bAR) adenylyl cyclase. This review will focus on the role of GPCRs, and in particular, adenosine receptors, in adipogenesis. Preadipocytes differentiate to mature adipocytes as the adipose tissue expands to compensate for the consumption of excess nutrients. These newly generated adipocytes contribute to maintaining metabolic homeostasis. Understanding the key drivers of this differentiation process can aid the development of therapeutics to combat the growing obesity epidemic and associated metabolic consequences. Although much literature has covered the transcriptional events that culminate in the formation of an adipocyte, less focus has been on receptor-mediated extracellular signals that direct this process. This review will highlight GPCRs and their downstream messengers as significant players controlling adipocyte differentiation.
Topics: Adipogenesis; Adipose Tissue; Animals; Gene Expression Regulation; Humans; Receptors, Purinergic P1
PubMed: 24114647
DOI: 10.1002/jcp.24473 -
Journal of Immunology Research 2023Dysregulation of adipogenesis is related to diabetic peripheral neuropathy (DPN) pathogenesis, which may be mediated by immune infiltration. Nevertheless, the expression...
Dysregulation of adipogenesis is related to diabetic peripheral neuropathy (DPN) pathogenesis, which may be mediated by immune infiltration. Nevertheless, the expression patterns of multiple adipogenesis-related genes and the differences of immune infiltration in different lipid metabolism levels remain unknown. GSE95849, a gene expression matrix containing DPN patients and healthy participants, was downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed adipogenesis-related genes (DEARGs) were screened by overlapping the adipogenesis-related genes with differentially expressed genes (DEGs). DPN patients from GSE24290 and GSE148059 were divided into two adipogenesis subgroups according to the expression of DEARGs. The single-sample gene set enrichment analysis (ssGSEA) was used to estimate the abundance of the immune cells between two subgroups. The analysis of immune infiltration suggested that a variety of immune cells and immune processes were elevated in the high expression group of DEARGs. The differentially expressed genes of the two subgroups were mainly enriched in biological processes and signaling pathways related to lipid metabolism. PPARG, FABP4, LIPE, FASN, SCD, DGAT2, PNPLA2, ADIPOQ, LEP, and CEBPA were identified as the hub genes of the two subgroups, whose related transcription factors (TFs) and miRNAs were predicted. An immunohistochemical assay was used to verify the expression of hub genes in DPN nerve tissues. Our comprehensive analysis of adipogenesis subgroups in DPN illustrated that different expression patterns of DEARGs may lead to different immune and inflammatory states. The identification of DEARGs may help to further distinguish the different characteristics of DPN patients and lay the foundation for targeted treatment. Our findings may bring a novel perspective to the diagnosis and treatment of DPN patients.
Topics: Humans; Adipogenesis; Databases, Factual; Diabetes Mellitus; Diabetic Neuropathies; MicroRNAs
PubMed: 36741233
DOI: 10.1155/2023/3673094 -
Current Opinion in Cell Biology Dec 2007Adipocyte differentiation consists of a complex series of events in which scores of cellular and extracellular factors interact to transform a fibroblast-like... (Review)
Review
Adipocyte differentiation consists of a complex series of events in which scores of cellular and extracellular factors interact to transform a fibroblast-like preadipocyte into a mature, lipid-filled adipocyte. Many of the pathways influencing this process have been identified using well-characterized preadipocyte culture systems and have subsequently been confirmed in animal models. Research conducted over the past decade has established the Wnt/beta-catenin signaling pathway as an important regulator of adipocyte differentiation. While initial reports implicated activators of Wnt/beta-catenin signaling as potent inhibitors of adipogenesis, recent investigations of mesenchymal cell fate, obesity, and type 2 diabetes highlight significant additional roles for Wnt signaling in metabolism and adipocyte biology.
Topics: Adipogenesis; Adipose Tissue; Animals; Cell Differentiation; Humans; Signal Transduction; Wnt Proteins; beta Catenin
PubMed: 17997088
DOI: 10.1016/j.ceb.2007.09.014 -
BMB Reports Apr 2022Obesity is caused by an imbalance between energy intake and energy expenditure. Exercise is attracting attention as one of the ways to treat obesity. Exercise induces...
Obesity is caused by an imbalance between energy intake and energy expenditure. Exercise is attracting attention as one of the ways to treat obesity. Exercise induces 'beige adipogenesis' in white adipose tissue, increasing total energy expenditure via energy dissipation in the form of heat. Also, beige adipogenesis can be induced by treatment with a beta-adrenergic receptor agonist. We developed a Cidea-dual reporter mouse (Cidea-P2ALuc2-T2A-tdTomato, Luciferase/tdTomato) model to trace and measure beige adipogenesis in vivo. As a result, both exercise and injection of beta-adrenergic receptor agonist induced beige adipogenesis and was detected through fluorescence and luminescence. We confirmed that exercise and beta-adrenergic receptor agonist induce beige adipogenesis in Cidea-dual reporter mouse, which will be widely used for detecting beige adipogenesis in vivo. [BMB Reports 2022; 55(4): 187-191].
Topics: Adipogenesis; Adipose Tissue, White; Animals; Apoptosis Regulatory Proteins; Mice; Obesity; Signal Transduction
PubMed: 35000670
DOI: 10.5483/BMBRep.2022.55.4.134 -
Nature Metabolism Jan 2022Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo...
Healthy adipose tissue remodeling depends on the balance between de novo adipogenesis from adipogenic progenitor cells and the hypertrophy of adipocytes. De novo adipogenesis has been shown to promote healthy adipose tissue expansion, which confers protection from obesity-associated insulin resistance. Here, we define the role and trajectory of different adipogenic precursor subpopulations and further delineate the mechanism and cellular trajectory of adipogenesis, using single-cell RNA-sequencing datasets of murine adipogenic precursors. We identify Rspo2 as a functional regulator of adipogenesis, which is secreted by a subset of CD142 cells to inhibit maturation of early progenitors through the receptor Lgr4. Increased circulating RSPO2 in mice leads to adipose tissue hypertrophy and insulin resistance and increased RSPO2 levels in male obese individuals correlate with impaired glucose homeostasis. Taken together, these findings identify a complex cellular crosstalk that inhibits adipogenesis and impairs adipose tissue homeostasis.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Computational Biology; Gene Expression Profiling; Gene Expression Regulation; Genetic Heterogeneity; Humans; Immunophenotyping; Insulin Resistance; Metabolic Networks and Pathways; Mice; Obesity; RNA-Seq; Receptors, G-Protein-Coupled; Recombinant Proteins; Stem Cells; Thrombospondins
PubMed: 35027768
DOI: 10.1038/s42255-021-00509-1 -
Frontiers in Endocrinology 2022Adipose tissue is essential for energy storage and endocrine regulation of metabolism. Imbalance in energy intake and expenditure result in obesity causing adipose... (Review)
Review
Adipose tissue is essential for energy storage and endocrine regulation of metabolism. Imbalance in energy intake and expenditure result in obesity causing adipose tissue dysfunction. This alters cellular composition of the stromal cell populations and their function. Moreover, the individual cellular composition of each adipose tissue depot, regulated by environmental factors and genetics, determines the ability of the depots to expand and maintain its endocrine and storage function. Thus, stromal cells modulate adipocyte function and vice versa. In this mini-review we discuss heterogeneity in terms of composition and fate of adipose progenitor subtypes and their interactions with and regulation by different immune cell populations. Immune cells are the most diverse cell populations in adipose tissue and play essential roles in regulating adipose tissue function interaction with adipocytes but also with adipocyte progenitors. We specifically discuss the role of macrophages, mast cells, innate lymphoid cells and T cells in the regulation of adipocyte progenitor proliferation, differentiation and lineage commitment. Understanding the factors and cellular interactions regulating preadipocyte expansion and fate decision will allow the identification of novel mechanisms and therapeutic strategies to promote healthy adipose tissue expansion without systemic metabolic impairment.
Topics: Adipocytes, White; Adipogenesis; Immunity, Innate; Lymphocytes; Stem Cells
PubMed: 35422761
DOI: 10.3389/fendo.2022.859044