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Nature Reviews. Molecular Cell Biology Apr 2019Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it... (Review)
Review
Obesity is characterized by increased adipose tissue mass and has been associated with a strong predisposition towards metabolic diseases and cancer. Thus, it constitutes a public health issue of major proportion. The expansion of adipose depots can be driven either by the increase in adipocyte size (hypertrophy) or by the formation of new adipocytes from precursor differentiation in the process of adipogenesis (hyperplasia). Notably, adipocyte expansion through adipogenesis can offset the negative metabolic effects of obesity, and the mechanisms and regulators of this adaptive process are now emerging. Over the past several years, we have learned a considerable amount about how adipocyte fate is determined and how adipogenesis is regulated by signalling and systemic factors. We have also gained appreciation that the adipogenic niche can influence tissue adipogenic capability. Approaches aimed at increasing adipogenesis over adipocyte hypertrophy can now be explored as a means to treat metabolic diseases.
Topics: Adipocytes; Adipogenesis; Animals; Cell Differentiation; Health; Humans; Obesity; Signal Transduction
PubMed: 30610207
DOI: 10.1038/s41580-018-0093-z -
Cell Death & Disease Jan 2023Obesity is strongly associated with metabolic diseases, which have become a global health problem. Exploring the underlying mechanism of adipogenesis is crucial for the...
Obesity is strongly associated with metabolic diseases, which have become a global health problem. Exploring the underlying mechanism of adipogenesis is crucial for the treatment of excess white fat. Oncogene YBX1 is a multifunctional DNA- and RNA-binding protein that regulates brown adipogenesis. However, the role of YBX1 in white adipogenesis and adipose tissue expansion remains unknown. Here, we showed that YBX1 deficiency inhibited murine and porcine adipocyte differentiation. YBX1 positively regulated adipogenesis through promoting ULK1- and ULK2-mediated autophagy. Mechanistically, we identified YBX1 serves as a 5-methylcytosine (mC)-binding protein directly targeting mC-containing Ulk1 mRNA by using RNA immunoprecipitation. RNA decay assay further proved that YBX1 upregulated ULK1 expression though stabilizing its mRNA. Meanwhile, YBX1 promoted Ulk2 transcription and expression as a transcription factor, thereby enhancing autophagy and adipogenesis. Importantly, YBX1 overexpression in white fat enhanced ULK1/ULK2-mediated autophagy and promoted adipose tissue expansion in mice. Collectively, these findings unveil the post-transcriptional and transcriptional mechanism and functional importance of YBX1 in autophagy and adipogenesis regulation, providing an attractive molecular target for therapies of obesity and metabolic diseases.
Topics: Animals; Mice; Adipogenesis; Autophagy; Gene Expression Regulation; Obesity; RNA, Messenger; Swine; Transcription Factors
PubMed: 36642732
DOI: 10.1038/s41419-023-05564-y -
Comprehensive Physiology Mar 2017Adipocytes are the defining cell type of adipose tissue. Once considered a passive participant in energy storage, adipose tissue is now recognized as a dynamic organ... (Review)
Review
Adipocytes are the defining cell type of adipose tissue. Once considered a passive participant in energy storage, adipose tissue is now recognized as a dynamic organ that contributes to several important physiological processes, such as lipid metabolism, systemic energy homeostasis, and whole-body insulin sensitivity. Therefore, understanding the mechanisms involved in its development and function is of great importance. Adipocyte differentiation is a highly orchestrated process which can vary between different fat depots as well as between the sexes. While hormones, miRNAs, cytoskeletal proteins, and many other effectors can modulate adipocyte development, the best understood regulators of adipogenesis are the transcription factors that inhibit or promote this process. Ectopic expression and knockdown approaches in cultured cells have been widely used to understand the contribution of transcription factors to adipocyte development, providing a basis for more sophisticated in vivo strategies to examine adipogenesis. To date, over two dozen transcription factors have been shown to play important roles in adipocyte development. These transcription factors belong to several families with many different DNA-binding domains. While peroxisome proliferator-activated receptor gamma (PPARγ) is undoubtedly the most important transcriptional modulator of adipocyte development in all types of adipose tissue, members of the CCAAT/enhancer-binding protein, Krüppel-like transcription factor, signal transducer and activator of transcription, GATA, early B cell factor, and interferon-regulatory factor families also regulate adipogenesis. The importance of PPARγ activity is underscored by several covalent modifications that modulate its activity and its ability to modulate adipocyte development. This review will primarily focus on the transcriptional control of adipogenesis in white fat cells and on the mechanisms involved in this fine-tuned developmental process. © 2017 American Physiological Society. Compr Physiol 7:635-674, 2017.
Topics: Adipocytes; Adipogenesis; Animals; CCAAT-Enhancer-Binding Proteins; Gene Expression Regulation; Humans; Kruppel-Like Transcription Factors; Metabolic Diseases; Models, Biological; PPAR gamma; Phosphorylation; Receptors, Steroid; STAT Transcription Factors; Serine; Sumoylation; Transcription, Genetic; Ubiquitination
PubMed: 28333384
DOI: 10.1002/cphy.c160022 -
Handbook of Experimental Pharmacology 2019Brown adipose tissue is well known to be a thermoregulatory organ particularly important in small rodents and human infants, but it was only recently that its existence... (Review)
Review
Brown adipose tissue is well known to be a thermoregulatory organ particularly important in small rodents and human infants, but it was only recently that its existence and significance to metabolic fitness in adult humans have been widely realized. The ability of active brown fat to expend high amounts of energy has raised interest in stimulating thermogenesis therapeutically to treat metabolic diseases related to obesity and type 2 diabetes. In parallel, there has been a surge of research aimed at understanding the biology of rodent and human brown fat development, its remarkable metabolic properties, and the phenomenon of white fat browning, in which white adipocytes can be converted into brown like adipocytes with similar thermogenic properties. Here, we review the current understanding of the developmental and metabolic pathways involved in forming thermogenic adipocytes, and highlight some of the many unknown functions of brown fat that make its study a rich and exciting area for future research.
Topics: Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Adult; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Thermogenesis
PubMed: 30203328
DOI: 10.1007/164_2018_168 -
Cell Metabolism Jul 2019The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or...
The precursor cells for metabolically beneficial beige adipocytes can alternatively become fibrogenic and contribute to adipose fibrosis. We found that cold exposure or β3-adrenergic agonist treatment of mice decreased the fibrogenic profile of precursor cells and stimulated beige adipocyte differentiation. This fibrogenic-to-adipogenic transition was impaired in aged animals, correlating with reduced adipocyte expression of the transcription factor PRDM16. Genetic loss of Prdm16 mimicked the effect of aging in promoting fibrosis, whereas increasing PRDM16 in aged mice decreased fibrosis and restored beige adipose development. PRDM16-expressing adipose cells secreted the metabolite β-hydroxybutyrate (BHB), which blocked precursor fibrogenesis and facilitated beige adipogenesis. BHB catabolism in precursor cells, mediated by BDH1, was required for beige fat differentiation in vivo. Finally, dietary BHB supplementation in aged animals reduced adipose fibrosis and promoted beige fat formation. Together, our results demonstrate that adipocytes secrete a metabolite signal that controls beige fat remodeling.
Topics: 3-Hydroxybutyric Acid; Adipocytes; Adipogenesis; Adipose Tissue, Beige; Animals; Blotting, Western; DNA-Binding Proteins; Flow Cytometry; Humans; In Vitro Techniques; Male; Mass Spectrometry; Mice; Transcription Factors
PubMed: 31155495
DOI: 10.1016/j.cmet.2019.05.005 -
Journal of Cachexia, Sarcopenia and... Oct 2023Intramuscular fat (IMF) and intramuscular connective tissue (IMC) are often seen in human myopathies and are central to beef quality. The mechanisms regulating their...
BACKGROUND
Intramuscular fat (IMF) and intramuscular connective tissue (IMC) are often seen in human myopathies and are central to beef quality. The mechanisms regulating their accumulation remain poorly understood. Here, we explored the possibility of using beef cattle as a novel model for mechanistic studies of intramuscular adipogenesis and fibrogenesis.
METHODS
Skeletal muscle single-cell RNAseq was performed on three cattle breeds, including Wagyu (high IMF), Brahman (abundant IMC but scarce IMF), and Wagyu/Brahman cross. Sophisticated bioinformatics analyses, including clustering analysis, gene set enrichment analyses, gene regulatory network construction, RNA velocity, pseudotime analysis, and cell-cell communication analysis, were performed to elucidate heterogeneities and differentiation processes of individual cell types and differences between cattle breeds. Experiments were conducted to validate the function and specificity of identified key regulatory and marker genes. Integrated analysis with multiple published human and non-human primate datasets was performed to identify common mechanisms.
RESULTS
A total of 32 708 cells and 21 clusters were identified, including fibro/adipogenic progenitor (FAP) and other resident and infiltrating cell types. We identified an endomysial adipogenic FAP subpopulation enriched for COL4A1 and CFD (log2FC = 3.19 and 1.92, respectively; P < 0.0001) and a perimysial fibrogenic FAP subpopulation enriched for COL1A1 and POSTN (log2FC = 1.83 and 0.87, respectively; P < 0.0001), both of which were likely derived from an unspecified subpopulation. Further analysis revealed more progressed adipogenic programming of Wagyu FAPs and more advanced fibrogenic programming of Brahman FAPs. Mechanistically, NAB2 drives CFD expression, which in turn promotes adipogenesis. CFD expression in FAPs of young cattle before the onset of intramuscular adipogenesis was predictive of IMF contents in adulthood (R = 0.885, P < 0.01). Similar adipogenic and fibrogenic FAPs were identified in humans and monkeys. In aged humans with metabolic syndrome and progressed Duchenne muscular dystrophy (DMD) patients, increased CFD expression was observed (P < 0.05 and P < 0.0001, respectively), which was positively correlated with adipogenic marker expression, including ADIPOQ (R = 0.303, P < 0.01; and R = 0.348, P < 0.01, respectively). The specificity of Postn/POSTN as a fibrogenic FAP marker was validated using a lineage-tracing mouse line. POSTN expression was elevated in Brahman FAPs (P < 0.0001) and DMD patients (P < 0.01) but not in aged humans. Strong interactions between vascular cells and FAPs were also identified.
CONCLUSIONS
Our study demonstrates the feasibility of beef cattle as a model for studying IMF and IMC. We illustrate the FAP programming during intramuscular adipogenesis and fibrogenesis and reveal the reliability of CFD as a predictor and biomarker of IMF accumulation in cattle and humans.
Topics: Cattle; Humans; Animals; Mice; Aged; Adipogenesis; Reproducibility of Results; Muscle, Skeletal; Cell Differentiation; Muscular Dystrophy, Duchenne
PubMed: 37439037
DOI: 10.1002/jcsm.13292 -
Cell Stem Cell Jul 2021Intramuscular fatty deposits, which are seen in muscular dystrophies and with aging, negatively affect muscle function. The cells of origin of adipocytes constituting...
Intramuscular fatty deposits, which are seen in muscular dystrophies and with aging, negatively affect muscle function. The cells of origin of adipocytes constituting these fatty deposits are mesenchymal stromal cells, fibroadipogenic progenitors (FAPs). We uncover a molecular fate switch, involving miR-206 and the transcription factor Runx1, that controls FAP differentiation to adipocytes. Mice deficient in miR-206 exhibit increased adipogenesis following muscle injury. Adipogenic differentiation of FAPs is abrogated by miR-206 mimics. Using a labeled microRNA (miRNA) pull-down and sequencing (LAMP-seq), we identified Runx1 as a miR-206 target, with miR-206 repressing Runx1 translation. In the absence of miR-206 in FAPs, Runx1 occupancy near transcriptional start sites of adipogenic genes and expression of these genes increase. We demonstrate that miR-206 mimicry in vivo limits intramuscular fatty infiltration. Our results provide insight into the underlying molecular mechanisms of FAP fate determination and formation of harmful fatty deposits in skeletal muscle.
Topics: Adipocytes; Adipogenesis; Animals; Cell Differentiation; Mesenchymal Stem Cells; Mice; MicroRNAs; Muscle, Skeletal
PubMed: 33945794
DOI: 10.1016/j.stem.2021.04.008 -
Best Practice & Research. Clinical... Mar 2023Thyroid-associated orbitopathy, the most common extrathyroidal manifestation of Graves' disease, is characterized by orbital inflammatory infiltration and activation of... (Review)
Review
Thyroid-associated orbitopathy, the most common extrathyroidal manifestation of Graves' disease, is characterized by orbital inflammatory infiltration and activation of orbital fibroblasts, which mediates de novo adipogenesis, excessive production of hyaluronan, myofibroblast differentiation and ultimately tissue fibrosis. Interactions among T cells, B cells, and orbital fibroblasts result in their activation and perpetuation of orbital inflammation as well as tissue remodelling. T helper 17 cells belong to a newly identified pathogenic CD4+ T cell subset which possesses prominent pro-inflammatory and profibrotic capabilities. Thyroid stimulating hormone receptor/insulin-like growth factor-1 receptor crosstalk and the downstream signalling pathways of both receptors represent the major mechanisms leading to activation of orbital fibroblasts. Thyroid stimulating hormone receptor autoantibody is the disease specific biomarker of great clinical relevance and utility. There is growing evidence that oxidative stress, gut microbiome and epigenetics also play a role in the pathogenesis and their manipulation may represent novel therapeutic strategies.
Topics: Humans; Graves Ophthalmopathy; Graves Disease; Receptors, Thyrotropin; T-Lymphocytes; Adipogenesis
PubMed: 35181241
DOI: 10.1016/j.beem.2022.101620 -
American Journal of Physiology. Cell... Mar 2022In recent years, technological advances have revealed a large potential number of long noncoding RNAs (lncRNAs). Findings recognize lncRNAs as orchestrating molecules in... (Review)
Review
In recent years, technological advances have revealed a large potential number of long noncoding RNAs (lncRNAs). Findings recognize lncRNAs as orchestrating molecules in a wide range of processes, at the transcriptional and posttranscriptional levels, although fewer studies address function. For differentiation, which consists of rearrangements in the gene expression profile and activation of stage- and cell type-dependent signaling mechanisms, the relevance of lncRNAs becomes crucial. The relationship between lncRNAs and key molecular factors in differentiation is strengthening; therefore the present review aims to comprehensively explain the role of lncRNAs in the signaling network involved in the main types of mesenchymal differentiation: adipogenesis, chondrogenesis, myogenesis, and osteogenesis. Notably, a step toward the integration of lncRNAs in the field of cell differentiation promises an exceptional impact.
Topics: Adipogenesis; Cell Differentiation; Mesenchymal Stem Cells; Osteogenesis; RNA, Long Noncoding
PubMed: 35080923
DOI: 10.1152/ajpcell.00364.2021 -
International Journal of Biological... Sep 2023Intramuscular fat content is closely related to the quality of beef, where the forkhead box protein O1 (FOXO1) is involved in adipocyte differentiation and lipid...
Intramuscular fat content is closely related to the quality of beef, where the forkhead box protein O1 (FOXO1) is involved in adipocyte differentiation and lipid metabolism, but the specific mechanism of its involvement is still unclear. In this study, interfering with FOXO1 promoted the G1/S transformation of bovine adipocytes by enhancing the expression of proliferation marker genes PCNA, CDK1, CDK2, CCNA2, CCNB1, and CCNE2, thereby positively regulating the proliferation of bovine adipocytes. Additionally, interfering with FOXO1 negatively regulated the expression of adipogenic differentiation marker genes PPARG and CEBPA, as well as lipid anabolism marker genes ACC, FASN, SCD1, SREBP1, FABP4, ACSL1, LPL, and DGAT1, thus reducing triglyceride (TG) content and inhibiting the generation of lipid droplets in bovine adipocytes. A combination of transcriptomic and metabolomics analyses revealed that FOXO1 could regulate the lipogenesis of cattle by influencing the AMPK and PI3K/AKT pathways. Importantly, chromatin immunoprecipitation (ChIP) and site-directed mutagenesis revealed that FOXO1 could regulate bovine lipogenesis by binding to the promoter regions of the CD36 and STEAP4 genes and affecting their transcriptional activities. These results provide a foundation for studying the role and molecular mechanism of FOXO1 in the bovine adipogenesis.
Topics: Cattle; Animals; Phosphatidylinositol 3-Kinases; Adipocytes; Lipid Metabolism; Adipogenesis; Gene Expression Profiling; Cell Differentiation
PubMed: 37506793
DOI: 10.1016/j.ijbiomac.2023.126025