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Cold Spring Harbor Perspectives in... Sep 2012Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in... (Review)
Review
Adipose tissue is an important site for lipid storage, energy homeostasis, and whole-body insulin sensitivity. It is important to understand the mechanisms involved in adipose tissue development and function, which can be regulated by the endocrine actions of various peptide and steroid hormones. Recent studies have revealed that white and brown adipocytes can be derived from distinct precursor cells. This review will focus on transcriptional control of adipogenesis and its regulation by several endocrine hormones. The general functions and cellular origins of adipose tissue and how the modulation of adipocyte development pertains to metabolic disease states will also be considered.
Topics: Adipocytes, Brown; Adipocytes, White; Adipogenesis; Adipose Tissue; Animals; Gene Regulatory Networks; Humans; Metabolic Diseases; Models, Biological; Signal Transduction
PubMed: 22952395
DOI: 10.1101/cshperspect.a008417 -
Physiological Reviews Oct 2018The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or... (Review)
Review
The subcutaneous adipose tissue (SAT) is the largest and best storage site for excess lipids. However, it has a limited ability to expand by recruiting and/or differentiating available precursor cells. When inadequate, this leads to a hypertrophic expansion of the cells with increased inflammation, insulin resistance, and a dysfunctional prolipolytic tissue. Epi-/genetic factors regulate SAT adipogenesis and genetic predisposition for type 2 diabetes is associated with markers of an impaired SAT adipogenesis and development of hypertrophic obesity also in nonobese individuals. We here review mechanisms for the adipose precursor cells to enter adipogenesis, emphasizing the role of bone morphogenetic protein-4 (BMP-4) and its endogenous antagonist gremlin-1, which is increased in hypertrophic SAT in humans. Gremlin-1 is a secreted and a likely important mechanism for the impaired SAT adipogenesis in hypertrophic obesity. Transiently increasing BMP-4 enhances adipogenic commitment of the precursor cells while maintained BMP-4 signaling during differentiation induces a beige/brown oxidative phenotype in both human and murine adipose cells. Adipose tissue growth and development also requires increased angiogenesis, and BMP-4, as a proangiogenic molecule, may also be an important feedback regulator of this. Hypertrophic obesity is also associated with increased lipolysis. Reduced lipid storage and increased release of FFA by hypertrophic SAT are important mechanisms for the accumulation of ectopic fat in the liver and other places promoting insulin resistance. Taken together, the limited expansion and storage capacity of SAT is a major driver of the obesity-associated metabolic complications.
Topics: Adipocytes; Adipogenesis; Adipose Tissue; Animals; Cell Differentiation; Diabetes Mellitus, Type 2; Humans; Inflammation; Insulin Resistance; Obesity
PubMed: 30067159
DOI: 10.1152/physrev.00034.2017 -
Endocrine Reviews Jan 2020Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central... (Review)
Review
Infants rely on brown adipose tissue (BAT) as a primary source of thermogenesis. In some adult humans, residuals of brown adipose tissue are adjacent to the central nervous system and acute activation increases metabolic rate. Brown adipose tissue (BAT) recruitment occurs during cold acclimation and includes secretion of factors, known as batokines, which target several different cell types within BAT, and promote adipogenesis, angiogenesis, immune cell interactions, and neurite outgrowth. All these processes seem to act in concert to promote an adapted BAT. Recent studies have also provided exciting data on whole body metabolic regulation with a broad spectrum of mechanisms involving BAT crosstalk with liver, skeletal muscle, and gut as well as the central nervous system. These widespread interactions might reflect the property of BAT of switching between an active thermogenic state where energy is highly consumed and drained from the circulation, and the passive thermoneutral state, where energy consumption is turned off. (Endocrine Reviews 41: XXX - XXX, 2020).
Topics: Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Adult; Animals; Cell Plasticity; Energy Metabolism; Humans; Infant; Muscle, Skeletal
PubMed: 31638161
DOI: 10.1210/endrev/bnz007 -
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 -
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 -
Nature Reviews. Molecular Cell Biology Sep 2011Adipose tissue, which is primarily composed of adipocytes, is crucial for maintaining energy and metabolic homeostasis. Adipogenesis is thought to occur in two stages:... (Review)
Review
Adipose tissue, which is primarily composed of adipocytes, is crucial for maintaining energy and metabolic homeostasis. Adipogenesis is thought to occur in two stages: commitment of mesenchymal stem cells to a preadipocyte fate and terminal differentiation. Cell shape and extracellular matrix remodelling have recently been found to regulate preadipocyte commitment and competency by modulating WNT and RHO-family GTPase signalling cascades. Adipogenic stimuli induce terminal differentiation in committed preadipocytes through the epigenomic activation of peroxisome proliferator-activated receptor-γ (PPARγ). The coordination of PPARγ with CCAAT/enhancer-binding protein (C/EBP) transcription factors maintains adipocyte gene expression. Improving our understanding of these mechanisms may allow us to identify therapeutic targets against metabolic diseases that are rapidly becoming epidemic globally.
Topics: Adipocytes; Adipogenesis; Animals; CCAAT-Enhancer-Binding Proteins; Cell Differentiation; Cell Lineage; Cell Shape; Epigenesis, Genetic; Extracellular Matrix; Humans; Mesenchymal Stem Cells; Models, Biological; PPAR gamma; Signal Transduction; Transforming Growth Factor beta; Wnt Signaling Pathway; rho GTP-Binding Proteins
PubMed: 21952300
DOI: 10.1038/nrm3198 -
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 -
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 -
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 -
Molecular Metabolism Aug 2022Regulation of proteasomal activity is an essential component of cellular proteostasis and function. This is evident in patients with mutations in proteasome subunits and...
OBJECTIVE
Regulation of proteasomal activity is an essential component of cellular proteostasis and function. This is evident in patients with mutations in proteasome subunits and associated regulators, who suffer from proteasome-associated autoinflammatory syndromes (PRAAS). These patients display lipodystrophy and fevers, which may be partly related to adipocyte malfunction and abnormal thermogenesis in adipose tissue. However, the cell-intrinsic pathways that could underlie these symptoms are unclear. Here, we investigate the impact of two proteasome subunits implicated in PRAAS, Psmb4 and Psmb8, on differentiation, function and proteostasis of brown adipocytes.
METHODS
In immortalized mouse brown pre-adipocytes, levels of Psmb4, Psmb8, and downstream effectors genes were downregulated through reverse transfection with siRNA. Adipocytes were differentiated and analyzed with various assays of adipogenesis, lipogenesis, lipolysis, inflammation, and respiration.
RESULTS
Loss of Psmb4, but not Psmb8, disrupted proteostasis and adipogenesis. Proteasome function was reduced upon Psmb4 loss, but partly recovered by the activation of Nuclear factor, erythroid-2, like-1 (Nfe2l1). In addition, cells displayed higher levels of surrogate inflammation and stress markers, including Activating transcription factor-3 (Atf3). Simultaneous silencing of Psmb4 and Atf3 lowered inflammation and restored adipogenesis.
CONCLUSIONS
Our study shows that Psmb4 is required for adipocyte development and function in cultured adipocytes. These results imply that in humans with PSMB4 mutations, PRAAS-associated lipodystrophy is partly caused by disturbed adipogenesis. While we uncover a role for Nfe2l1 in the maintenance of proteostasis under these conditions, Atf3 is a key effector of inflammation and blocking adipogenesis. In conclusion, our work highlights how proteasome dysfunction is sensed and mitigated by the integrated stress response in adipocytes with potential relevance for PRAAS patients and beyond.
Topics: Adipocytes, Brown; Adipogenesis; Animals; Inflammation; Lipodystrophy; Mice; Proteasome Endopeptidase Complex
PubMed: 35636710
DOI: 10.1016/j.molmet.2022.101518