Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice

Min, So Yun; Kady, Jamie; Nam, Minwoo; Rojas-Rodriguez, Raziel; Berkenwald, Aaron; Kim, Jong Hun; Noh, Hye Lim; Kim, Jason K.; Cooper, Marcus P.; Fitzgibbons, Timothy P.; Brehm, Michael A.; Corvera, Silvia

doi:10.1038/nm.4031

Cited by 278 publications

(266 citation statements)

References 41 publications

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“…Recent studies have also shown that BAT transplantation corrects metabolic phenotypes, and improves type 1 diabetes in streptozotocin-treated mice as well as HFD-induced insulin resistance in mice (Gunawardana & Piston 2012, Stanford et al 2013. Consistently, implantation of human beige adipocytes improves systemic glucose tolerance in HFD-induced glucose-intolerant mice (Min et al 2016). Given that preadipocytes or stem cells are also able to be differentiated into mature brown or beige adipocytes, brown or beige adipocytes transplantation may offer a practicable means for the treatment of obesity and diabetes (Bayindir et al 2015).…”

Section: :3mentioning

confidence: 97%

“…In line with this, ablation of UCP1 results in disruption of diet-induced thermogenesis and exacerbation of diet-induced obesity in mice exempt from thermal stress by living at thermoneutrality (Feldmann et al 2009). Furthermore, the implantation of human beige adipocyte acquired from beige progenitors into high-fat diet (HFD)-fed mice improves systemic glucose tolerance (Min et al 2016).…”

Section: Thermogenic Function Of Brown and Beige Adipose Tissuementioning

confidence: 99%

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Adipose tissue in control of metabolism

Luo

Liu

2016

Journal of Endocrinology

479

331

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Adipose tissue plays a central role in regulating whole-body energy and glucose homeostasis through its subtle functions at both organ and systemic levels. On one hand, adipose tissue stores energy in the form of lipid and controls the lipid mobilization and distribution in the body. On the other hand, adipose tissue acts as an endocrine organ and produces numerous bioactive factors such as adipokines that communicate with other organs and modulate a range of metabolic pathways. Moreover, brown and beige adipose tissue burn lipid by dissipating energy in the form of heat to maintain euthermia, and have been considered as a new way to counteract obesity. Therefore, adipose tissue dysfunction plays a prominent role in the development of obesity and its related disorders such as insulin resistance, cardiovascular disease, diabetes, depression and cancer. In this review, we will summarize the recent findings of adipose tissue in the control of metabolism, focusing on its endocrine and thermogenic function.

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Section: :3mentioning

confidence: 97%

Section: Thermogenic Function Of Brown and Beige Adipose Tissuementioning

confidence: 99%

Adipose tissue in control of metabolism

Luo

Liu

2016

Journal of Endocrinology

479

331

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“…Although the molecular characteristics and beiging potential of eWAsc were adequately explored, more detail is required in exploring the regulation mechanism. Similar therapies have been performed in mice by using induced mature human brown/beige adipocytes [30,42]. Although we have demonstrated that eWAsc has excellent browning potential and functionality, these human embryo-derived stem cells or adipocytes are still difficult to apply in clinical practice due to ethical and technical limitations.…”

Section: Discussionmentioning

confidence: 87%

“…Therapeutic methods targeting brown adipocytes/beige adipocytes are providing new avenues in therapies for obesity and related diseases. Although the characteristics of human adipocytes have been studied [14,17,30,31], the research related to human brown or beige adipocytes is not comprehensive, especially in terms of their characteristics, sources, development, functions, and applications. Importantly, compared to brown adipocytes, the ability to generate and isolate beige adipocytes from white adipose tissue is a growing field of research.…”

Section: Discussionmentioning

confidence: 99%

Characterization and Beige Adipogenic Potential of Human Embryo White Adipose Tissue-Derived Stem Cells

Zhang

Wang

et al. 2018

Cell Physiol Biochem

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Background/Aims: Brown and beige adipocytes are widely recognized as potential therapeutic targets to treat obesity and related metabolic disorders, and the recruitment of brown and beige adipocytes is an essential aspect that requires attention. Although many methods of activating brown adipocytes or generating beige adipocytes have been reported, the limited number and sources are the biggest challenges. The number of white adipocytes is much greater than the number of brown adipocytes, both in human adults and fetuses. Unfortunately, human adult white adipose tissue-derived stem cell (aWAsc) has little beige adipogenic potential. However, the characteristics and beige adipogenic potential of human embryo-derived white adipose stem cells (eWAsc) still need to be investigated. Methods: To analyze the characteristics and functionality of eWAsc, we analyzed the markers of adipose precursor cells by flow cytometry. Then, differentiation and browning/beiging were induced, and the identifying markers were analyzed by real-time PCR and immunoblot. In addition, more in-depth exploration was performed using RNA-SEQ on eWAsc and aWAsc. Results: eWAsc was isolated from human embryonic white adipose tissue, and aWAsc was isolated from adult white adipose tissue by collagenase treatment. eWAsc has extreme advantages in adipogenesis capacity and browning/beiging ability in comparison to aWAsc, indicating that eWAsc may possess some special regulatory factors to promote the generation of functional brown/beige adipocytes. Greater exploration was enabled by RNA-SEQ, revealing a large number of differences at the transcriptional levels, including 1263 differentially expressed genes, 657 down- and 605 upregulated, in eWAsc compared to aWAsc. Pathway analysis revealed enrichment in cell cycle, TGF-β signaling pathway, DNA replication, and Hippo signaling pathways. Interestingly, the expression levels of C/EBPα, FGF1 and FST gene, which are related to the maturation of adipocytes, Hippo signaling pathway and TGF-β signaling pathway, were significantly higher in eWAsc than in aWAsc. These may be potential candidates and possible regulatory targets for recruiting beige adipocytes in human adipose tissue. Conclusion: Overall, we have demonstrated the molecular characteristics and excellent beige adipogenic potential of eWAsc, providing a new reference for studying human adipocytes.

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“…Maintenance of a capillary network is critically important for its metabolic function as well as survival of engrafted tissue. There is increasing evidence that angiogenic factors modu late the brown/beige differentiation and its survival after transplantation [31,32]. On the other hand, the microenvironment of the 3D culture conditions, such as stiffness or porosity of the matrix, have shown to affect the behavior of the white adipocytes [33–35].…”

Section: Introductionmentioning

confidence: 99%

Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function

Kuss

Kim

et al. 2018

Acta Biomaterialia

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Obesity and its related health complications cause billions of dollars in healthcare costs annually in the United States, and there are yet to be safe and long-lasting anti-obesity approaches. Using brown adipose tissue (BAT) is a promising approach, as it uses fats for energy expenditure. However, the effect of the microenvironment on human thermogenic brown adipogenesis and how to generate clinically relevant sized and functioning BAT are still unknown. In our current study, we evaluated the effects of endothelial growth medium exposure on brown adipogenesis of human brown adipose progenitors (BAP). We found that pre-exposing BAP to angiogenic factors promoted brown adipogenic differentiation and metabolic activity. We further 3D bioprinted brown and white adipose progenitors within hydrogel-based bioink with controllable physicochemical properties and evaluated the cell responses in 3D bioprinted environments. We used soft, stiff, and stiff-porous constructs to encapsulate the cells. All three types had high cell viability and allowed for varying levels of function for both white and brown adipocytes. We found that the soft hydrogel constructs promoted white adipogenesis, while the stiff-porous hydrogel constructs improved both white and brown adipogenesis and were the optimal condition for promoting brown adipogenesis. Consistently, stiff-porous hydrogel constructs showed higher metabolic activities than stiff hydrogel constructs, as assessed by 2-deoxy glucose uptake (2-DOG) and oxygen consumption rate (OCR). These findings show that the physicochemical environments affect the brown adipogenesis and metabolic function, and further tuning will be able to optimize their functions. Our results also demonstrate that 3D bioprinting of brown adipose tissues with clinically relevant size and metabolic activity has the potential to be a viable option in the treatment of obesity and type 2 diabetes.

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Human 'brite/beige' adipocytes develop from capillary networks, and their implantation improves metabolic homeostasis in mice

Cited by 278 publications

References 41 publications

Adipose tissue in control of metabolism

Adipose tissue in control of metabolism

Characterization and Beige Adipogenic Potential of Human Embryo White Adipose Tissue-Derived Stem Cells

Effects of tunable, 3D-bioprinted hydrogels on human brown adipocyte behavior and metabolic function

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