Genetic Markers of Brown Adipose Tissue Identity and <i>In Vitro</i> Brown Adipose Tissue Activity in Humans

Nascimento, Emmani B. M.; Sparks, Lauren M.; Divoux, Adeline; Gisbergen, Marike W. van; Broeders, Evie P. M.; Jörgensen, Johanna A.; Schaart, Gert; Bouvy, Nicole D.; Lichtenbelt, Wouter D. van Marken; Schrauwen, Patrick

doi:10.1002/oby.22062

Cited by 29 publications

(24 citation statements)

References 26 publications

(41 reference statements)

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“…4E,F). According to a recent report that the expression level of a classical brown adipocyte marker, Zic1, was negatively associated with human BAT activity 35 , ciBAs significantly reduced the expression ( Fig. 4G).…”

Section: Discussionmentioning

confidence: 67%

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: 67%

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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“…Differentiation into adipocytes did not appreciably alter expression of any neuregulin ( Figure 1A). We used an additional marker of WAT, UCP2, which we found in both human and mouse cells as demonstrating these cells are WAT [19] , not BAT (BAT preferentially expresses UCP1 [20] ). Our previously published analysis demonstrates that perilipin-1, leptin, and other genes behave as expected upon adipogenic differentiation in this cell line [21] .…”

Section: Resultsmentioning

confidence: 99%

Epigenetic regulation of Neuregulin-1 tunes white adipose stem cell differentiation

Cordero

Callihan

Said

et al. 2020

Preprint

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AbstractExpansion of subcutaneous adipose tissue by differentiation of new adipocytes has been linked to improvements in metabolic health. However, an expandability limit has been observed wherein new adipocytes cannot be produced, the existing adipocytes become enlarged (hypertrophic) and lipids spill over into ectopic sites. Inappropriate ectopic storage of these surplus lipids in liver, muscle, and visceral depots has been linked with metabolic dysfunction. Here we show that Neuregulin-1 (NRG1) serves as a regulator of adipogenic differentiation in subcutaneous primary human stem cells. We further demonstrate that DNA methylation modulates NRG1 expression in these cells, and a 3-day exposure of stem cells to a recombinant NRG1 peptide fragment is sufficient to reprogram adipogenic cellular differentiation to higher levels. These results define a novel molecular adipogenic rheostat with potential implications for the expansion of adipose tissue in vivo.

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“…Those effects were not different from the ones elicited by adiponectin, for genistein concentration up to 1 μM. Meanwhile, genistein increased the browning of pre-adipocytes, as shown by the augmented UCP1 expression [ 29 , 30 ].…”

Section: Discussionmentioning

confidence: 99%

Effects of Genistein on Differentiation and Viability of Human Visceral Adipocytes

et al. 2018

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Obesity can lead to pathological growth of adipocytes by inducing inflammation and oxidative stress. Genistein could be a potential candidate for the treatment of obesity due to its antioxidant properties. Specific kits were used to examine the effects of genistein vs adiponectin on human visceral pre-adipocytes differentiation, cell viability, mitochondrial membrane potential, and oxidative stress in pre-adipocytes and in white/brown adipocytes. Western Blot was performed to examine changes in protein activation/expression. Genistein increased human visceral pre-adipocytes differentiation and browning, and caused a dose-related improvement of cell viability and mitochondrial membrane potential. Similar effects were observed in brown adipocytes and in white adipocytes, although in white cells the increase of cell viability was inversely related to the dose. Moreover, genistein potentiated AMP-activated protein kinase (AMPK)/mitofusin2 activation/expression in pre-adipocytes and white/brown adipocytes and protected them from the effects of hydrogen peroxide. The effects caused by genistein were similar to those of adiponectin. The results obtained showed that genistein increases human visceral pre-adipocytes differentiation and browning, protected against oxidative stress in pre-adipocytes and white/brown adipocytes through mechanisms related to AMPK-signalling and the keeping of mitochondrial function.

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Genetic Markers of Brown Adipose Tissue Identity and In Vitro Brown Adipose Tissue Activity in Humans

Cited by 29 publications

References 26 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

Epigenetic regulation of Neuregulin-1 tunes white adipose stem cell differentiation

Effects of Genistein on Differentiation and Viability of Human Visceral Adipocytes

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