Molecular signatures and functional analysis of beige adipocytes induced from in vivo intra-abdominal adipocytes

Xue, Huiling; Wang, Zhe; Hua, Yongjie; Ke, Shanshan; Wang, Yao; Zhang, Junpeng; Pan, Yi-Hsuan; Huang, Wenjie; Irwin, David M.; Zhang, Shuyi

doi:10.1126/sciadv.aar5319

Cited by 20 publications

(12 citation statements)

References 40 publications

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“…Compared with Ctrl-Adi, Suc-Adi are enriched with genes associated with beige adipocytes, although less in the representative genes related to white adipocytes (Fig. 6B) (30)(31)(32). Accordingly, pathway enrichment analysis demonstrated that the PI3K-Akt pathway and the AMPK pathway were altered in adipocytes differentiated from ADSCs with succinate treatment, further supporting succinate-treated ADSCs with a strong preference to generate beige adipocytes (SI Appendix, Fig.…”

Section: Robust Mitochondrial Complex II Activity In Scd1-deficient Adscsmentioning

confidence: 71%

Scd1 controls de novo beige fat biogenesis through succinate-dependent regulation of mitochondrial complex II

Liu

Lin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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Preadipocytes can give rise to either white adipocytes or beige adipocytes. Owing to their distinct abilities in nutrient storage and energy expenditure, strategies that specifically promote “beiging” of adipocytes hold great promise for counterbalancing obesity and metabolic diseases. Yet, factors dictating the differentiation fate of adipocyte progenitors remain to be elucidated. We found that stearoyl-coenzyme A desaturase 1 (Scd1)-deficient mice, which resist metabolic stress, possess augmentation in beige adipocytes under basal conditions. Deletion of Scd1 in mature adipocytes expressing Fabp4 or Ucp1 did not affect thermogenesis in mice. Rather, Scd1 deficiency shifted the differentiation fate of preadipocytes from white adipogenesis to beige adipogenesis. Such effects are dependent on succinate accumulation in adipocyte progenitors, which fuels mitochondrial complex II activity. Suppression of mitochondrial complex II by Atpenin A5 or oxaloacetic acid reverted the differentiation potential of Scd1-deficient preadipocytes to white adipocytes. Furthermore, supplementation of succinate was found to increase beige adipocyte differentiation both in vitro and in vivo. Our data reveal an unappreciated role of Scd1 in determining the cell fate of adipocyte progenitors through succinate-dependent regulation of mitochondrial complex II.

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Section: Robust Mitochondrial Complex II Activity In Scd1-deficient Adscsmentioning

confidence: 71%

Scd1 controls de novo beige fat biogenesis through succinate-dependent regulation of mitochondrial complex II

Liu

Lin

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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“…Besides, H&E staining revealed significantly smaller adipocytes size in the E2F1 –/– WAT compared with WT WAT, which presented “beige” adipose-like morphology. As Xue et al reported that after exposure to cold temperatures, subcutaneous WAT of mice possessed relatively large, round, and condensed mitochondria with numerous transverse cristae surrounding smaller lipid droplets, indicating browning of WAT ( Xue et al, 2018 ). Here, E2F1 –/– WAT showed smaller intracellular lipid droplets and more mitochondria quantities than WT WAT, revealing the beige adipose shape.…”

Section: Discussionmentioning

confidence: 99%

Transcription Factor E2F1 Knockout Promotes Mice White Adipose Tissue Browning Through Autophagy Inhibition

Xiong

Tan

et al. 2021

Front. Physiol.

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Obesity is associated with energy metabolic disturbance and is caused by long-term excessive energy storage in white adipose tissue (WAT). The WAT browning potentially reduces excessive energy accumulation, contributing an attractive target to combat obesity. As a pivotal regulator of cell growth, the transcription factor E2F1 activity dysregulation leads to metabolic complications. The regulatory effect and underlying mechanism of E2F1 knockout on WAT browning, have not been fully elucidated. To address this issue, in this study, the in vivo adipose morphology, mitochondria quantities, uncoupling protein 1 (UCP-1), autophagy-related genes in WAT of wild-type (WT) and E2F1–/– mice were detected. Furthermore, we evaluated the UCP-1, and autophagy-related gene expression in WT and E2F1–/– adipocyte in vitro. The results demonstrated that E2F1 knockout could increase mitochondria and UCP-1 expression in WAT through autophagy suppression in mice, thus promoting WAT browning. Besides, adipocytes lacking E2F1 showed upregulated UCP-1 and downregulated autophagy-related genes expression in vitro. These results verified that E2F1 knockout exerted effects on inducing mice WAT browning through autophagy inhibition in vivo and in vitro. These findings regarding the molecular mechanism of E2F1-modulated autophagy in controlling WAT plasticity, provide a novel insight into the functional network with the potential therapeutic application against obesity.

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“…The present study revealed a previously unrecognized role of LETM1 in obesity-related hypertension by acting as a mitochondrial Ca 2+ modulator in BAT. In addition, LETM1 is also required for the browning of WAT to form beige adipocytes, indicating a promotional effect of LETM1 in the maintenance of BAT [ 33 ]. In our study, we observed that the knockout of TRPV1 directly upregulated the expression of both UCP1 and LETM1, suggesting that TRPV1 is involved in controlling the normal activity of BAT, which might be related to its regulatory effect on sympathetic nerves, as the activation of TRPV1 in the nucleus tractus solitarius has been reported to inhibit BAT sympathetic nerve activity and decrease BAT metabolism [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Lack of TRPV1 aggravates obesity-associated hypertension through the disturbance of mitochondrial Ca2+ homeostasis in brown adipose tissue

Luo

et al. 2022

Hypertens Res

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The combination of obesity and hypertension is associated with high morbidity and mortality; however, the mechanism underlying obesity-induced hypertension remains unclear. In this study, we detected the possible effects of TRPV1, a previously identified antihypertensive calcium (Ca2+) channel in adipose tissue, on the occurrence of obesity and hypertension in mice lacking UCP1, a spontaneously genetically manipulated obesity model, by generating TRPV1 and UCP1 double knockout mice. In these mice, obesity and hypertension appeared earlier and were more severe than in mice with the knockout of UCP1 or TRPV1 alone. The knockout of TRPV1 in UCP1 knockout mice further reduced functional brown adipose tissue (BAT) generation; decreased resting oxygen consumption, heat production, and locomotor activities; and was accompanied by severe mitochondrial respiratory dysfunction in BAT. Mechanistically, TRPV1, UCP1, and LETM1 acted as a complex to maintain an appropriate mitochondrial Ca2+ level, and TRPV1 knockout caused a compensatory increase in mitochondrial Ca2+ uptake via LETM1 activation. However, the compensatory response was blocked in UCP1−/− mice, resulting in dramatically reduced mitochondrial Ca2+ uptake and higher production of ATP and oxidative stress. This study provides in vivo evidence for the critical role of BAT mitochondrial Ca2+ homeostasis in obesity-associated hypertension and indicates that the TRPV1/UCP1/LETM1 complex may be an alternative intervention target.

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Molecular signatures and functional analysis of beige adipocytes induced from in vivo intra-abdominal adipocytes

Abstract: Bat and mouse beige adipocytes induced from white adipocytes provide insights into therapy against obesity-related disease.

Cited by 20 publications

References 40 publications

Scd1 controls de novo beige fat biogenesis through succinate-dependent regulation of mitochondrial complex II

Scd1 controls de novo beige fat biogenesis through succinate-dependent regulation of mitochondrial complex II

Transcription Factor E2F1 Knockout Promotes Mice White Adipose Tissue Browning Through Autophagy Inhibition

Lack of TRPV1 aggravates obesity-associated hypertension through the disturbance of mitochondrial Ca2+ homeostasis in brown adipose tissue

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