Transcriptional and Epigenomic Regulation of Adipogenesis

Lee, Ji-Eun; Schmidt, Hannah; Lai, Binbin; Ge, Kai

doi:10.1128/mcb.00601-18

Cited by 206 publications

(201 citation statements)

References 171 publications

(162 reference statements)

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“…In this study, both Rosiglitazone and Forskolin play a critical role in the direct conversion and Ucp1 expression. Peroxisome proliferator-activated receptor gamma, PPARγ, activated by the selective agonist, Rosiglitazone, functions with other transcription factors and epigenetic regulators as a master transcription factor for adipogenesis 26 . Increased cellular levels of cAMP by Forskolin induce not only PKA-mediated phosphorylation of CREB www.nature.com/scientificreports www.nature.com/scientificreports/ but also P38 MAP kinase-mediated phosphorylation of ATF2 27 .…”

Section: Discussionmentioning

confidence: 99%

A developed serum-free medium and an optimized chemical cocktail for direct conversion of human dermal fibroblasts into brown adipocytes

Takeda

Dai

2020

Sci Rep

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A developed serum-free medium and an optimized chemical cocktail for direct conversion of human dermal fibroblasts into brown adipocytes Yukimasa takeda & ping Dai * Brown adipocytes coordinate systemic energy metabolism associated with the pathogenesis of obesity and related metabolic diseases including type 2 diabetes. We have previously reported chemical compound-induced brown adipocytes (ciBAs) converted from human dermal fibroblasts without using transgenes. In this study, to reveal a precise molecular mechanism underlying the direct conversion and human adipocyte browning, we developed serum-free brown adipogenic medium (SFBAM) with an optimized chemical cocktail consisting of Rosiglitazone, Forskolin, and BMP7. During the direct conversion, treatment with BMP7 enhanced Ucp1 expression rather than the conversion efficiency in the absence of BMP signalling inhibitors. Moreover, treatment with a TGF-β signalling pathway inhibitor was no longer required in the serum-free medium, likely because the TGF-β pathway was already suppressed. SFBAM and the chemical cocktail efficiently converted human dermal fibroblasts into ciBAs within four weeks. The ciBAs exhibited increased mitochondrial levels, elevated oxygen consumption rate, and a response to β-adrenergic receptor agonists. Thus the ciBAs converted by the serum-free medium and the chemical cocktail provide a novel model of human brown (beige) adipocytes applicable for basic research, drug screening, and clinical applications.Direct lineage reprogramming is an attractive approach to rapidly prepare desired cell types from patient-derived autologous somatic cells for transplantation therapy bypassing a pluripotent state 1,2 . So far human fibroblasts have been directly converted into myoblasts, cardiomyocytes, hepatocytes, and neurons by overexpression of a specific set of transcription factors 3-6 . The fibroblasts could also be converted to brown adipocytes by overexpression of two transcription factors, C/EBP-β and C-Myc 7 . However, in general direct reprogramming with virus vector-mediated overexpression of multiple transcription factors requires complicated procedures and also increases the risk of genomic instability and subsequent tumor formation 8 . Accumulating evidence has suggested that small molecules enable efficient cellular differentiation and direct reprogramming by modulating activity of target transcription factors as well as major signalling pathways 9,10 . We have previously reported that neuronal cells and brown adipocyte-like cells were converted from human fibroblasts by small molecules only without the use of transgene 11,12 . In addition, combinations of small molecules only also enable conversion of human fibroblasts into astrocytes, Schwann cells, osteoblasts, and cardiomyocytes [13][14][15][16] . Such simple and reproducible techniques for direct reprogramming are promising for the preparation of target cells with a reduced risk of mutations and tumorigenesis for transplantation therapy and other clinical applications 1 .Two types o...

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Section: Discussionmentioning

confidence: 99%

A developed serum-free medium and an optimized chemical cocktail for direct conversion of human dermal fibroblasts into brown adipocytes

Takeda

Dai

2020

Sci Rep

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“…We are aware that our AdipoqER/Td data conflict with a previous study suggesting that Adipoq-CreER labeled cells are adipoprogenitors with CFU-F forming ability 43 . The discrepancy might lie in different ages of mice, different 24 bone marrow harvest methods, different culture conditions, and probably different criteria of defining CFU-Fs. Nevertheless, our CFU-F data match with our computational cell cycle results, in vivo EdU incorporation, and the general consensus that Adipoq-Cre(ER) labels mature adipocytes only 40 .…”

Section: Mscs In Bone Marrow Is Still Ambiguous Since Lepr + Cells Amentioning

confidence: 99%

Single cell transcriptomics identifies a unique adipocyte population that regulates bone marrow environment

Zhong

Yao

Tower

et al. 2019

Preprint

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Bone marrow mesenchymal lineage cells are a heterogeneous cell population involved in bone homeostasis and diseases such as osteoporosis. While it is long postulated that they originate from mesenchymal stem cells (MSCs), the true identity of MSCs and their in vivo bifurcated differentiation routes into osteoblasts and adipocytes remain poorly understood. Here, by employing single cell transcriptome analysis, we identified MSCs and delineated their bilineage differentiation paths in young, adult and aging mice. Among several newly discovered mesenchymal subpopulations, one is a distinct population of adipose-lineage cells that we named marrow environment regulating adipose cells (MERAs). MERAs are non-proliferative, postprogenitor cells that express many mature adipocyte markers but are devoid of lipid droplets. They are abundant in the bone marrow of young mice, acting as pericytes and stromal cells that form numerous connections among themselves and with other cells inside bone, including endothelial cells. Genetic ablation of MERAs disrupts marrow vessel structure, promotes de novo bone formation. Taken together, MERAs represent a unique population of adipose lineage cells that exist only in the bone marrow with critical roles in regulating bone and vessel homeostasis.

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“…Because histone acetylation modulates a myriad of cellular and metabolic pathways, a dysregulation of the expression and activities of HATs and HDACs have been implicated in various pathological conditions including cancers (52,(58)(59)(60), neurological disorders (50,(61)(62)(63), autoimmune diseases (54,(64)(65)(66)(67), and in particular relevance to this review, obesity, and its metabolic comorbidities such as inflammation, insulin resistance, and liver steatosis (25). Given their importance in regulating gene expression and their potential as attractive therapeutic targets for the treatment of metabolic diseases, several key HATs, and HDACs have been identified by researchers for their involvement in adipogenesis (39). This review will focus only on those that are involved in the regulation of thermogenic adipocyte differentiation, adaptive thermogenesis and the pathogenesis of metabolic disorders (Figure 1B).…”

Section: Overview Of Histone Acetylation and Deacetylationmentioning

confidence: 99%

“…Histone acetylation and deacetylation are catalyzed by HATs and HDACs, respectively (39,(41)(42)(43)(44). In general, multiple lysine residues on histones 3 and 4 are acetylated during transcriptional activation (i.e., H3K9, H3K14, H3K18, H3K23, H3K27, H3K56, and H4K5, H4K8, H4K12, H4K16) (40,42,43,(45)(46)(47).…”

Section: Overview Of Histone Acetylation and Deacetylationmentioning

confidence: 99%

“…Of the aforementioned epigenetics alterations, an increasing number of studies have pointed to the effects of histone modifications-in particular, histone acetylation-on adipocyte differentiation and adipogenesis (30,(36)(37)(38)(39)(40). Following which, in the recent years, the role of histone acetyltransferases (HATs) and histone deacetylases (HDACs) in the regulation of the development and function of thermogenic adipocytes have garnered remarkable interest from scientists and clinicians for their therapeutic potential in ameliorating obesity and its complications.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

et al. 2020

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Over the past decade, the increasing prevalence of obesity and its associated metabolic disorders constitutes one of the most concerning healthcare issues for countries worldwide. In an effort to curb the increased mortality and morbidity derived from the obesity epidemic, various therapeutic strategies have been developed by researchers. In the recent years, advances in the field of adipocyte biology have revealed that the thermogenic adipose tissue holds great potential in ameliorating metabolic disorders. Additionally, epigenetic research has shed light on the effects of histone acetylation on adipogenesis and thermogenesis, thereby establishing the essential roles which histone acetyltransferases (HATs) and histone deacetylases (HDACs) play in metabolism and systemic energy homeostasis. In regard to the therapeutic potential of thermogenic adipocytes for the treatment of metabolic diseases, herein, we describe the current state of knowledge of the regulation of thermogenic adipocyte differentiation and adaptive thermogenesis through histone acetylation. Furthermore, we highlight how different HATs and HDACs maintain the epigenetic transcriptional network to mediate the pathogenesis of various metabolic comorbidities. Finally, we provide insights into recent advances of the potential therapeutic applications and development of HAT and HDAC inhibitors to alleviate these pathological conditions.

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Transcriptional and Epigenomic Regulation of Adipogenesis

Cited by 206 publications

References 171 publications

A developed serum-free medium and an optimized chemical cocktail for direct conversion of human dermal fibroblasts into brown adipocytes

A developed serum-free medium and an optimized chemical cocktail for direct conversion of human dermal fibroblasts into brown adipocytes

Single cell transcriptomics identifies a unique adipocyte population that regulates bone marrow environment

Regulation of Thermogenic Adipocyte Differentiation and Adaptive Thermogenesis Through Histone Acetylation

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