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| 2. |
- Du, QQ, et al.
(författare)
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Generation of mega brown adipose tissue in adults by controlling brown adipocyte differentiation in vivo
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:40, s. e2203307119-
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Tidskriftsartikel (refereegranskat)abstract
- Brown adipose tissue (BAT) is a highly specialized adipose tissue in its immobile location and size during the entire adulthood. In response to cold exposure and other β3-adrenoreceptor stimuli, BAT commits energy consumption by nonshivering thermogenesis (NST). However, the molecular machinery in controlling the BAT mass in adults is unknown. Here, we show our surprising findings that the BAT mass and functions can be manipulated in adult animals by controlling BAT adipocyte differentiation in vivo. Platelet-derived growth factor receptor α (PDGFα) expressed in BAT progenitor cells served a signaling function to avert adipose progenitor differentiation. Genetic and pharmacological loss-of-function of PDGFRα eliminated the differentiation barrier and permitted progenitor cell differentiation to mature and functional BAT adipocytes. Consequently, an enlarged BAT mass (megaBAT) was created by PDGFRα inhibition owing to increases of brown adipocyte numbers. Under cold exposure, a microRNA-485 (miR-485) was identified as a master suppressor of the PDGFRα signaling, and delivery of miR-485 also produced megaBAT in adult animals. Noticeably, megaBAT markedly improved global metabolism, insulin sensitivity, high-fat-diet (HFD)-induced obesity, and diabetes by enhancing NST. Together, our findings demonstrate that the adult BAT mass can be increased by blocking the previously unprecedented inhibitory signaling for BAT progenitor cell differentiation. Thus, blocking the PDGFRα for the generation of megaBAT provides an attractive strategy for treating obesity and type 2 diabetes mellitus (T2DM).
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| 3. |
- Hedlund, EM, et al.
(författare)
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Malignant cell-derived PlGF promotes normalization and remodeling of the tumor vasculature
- 2009
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 106:41, s. 17505-17510
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Tidskriftsartikel (refereegranskat)abstract
- Vascular functions of PlGF remain poorly understood and controversial. Here, we show that tumor cell-derived PlGF-1 and PlGF-2 displayed significant remodeling effects on the tumor vasculature, leading to a normalized vascular phenotype and improved functions against leakage. In two murine tumor models, that is, T241 fibrosarcoma and Lewis lung carcinoma, stable expression of PlGF-1 and PlGF-2 in tumor cells resulted in significant reduction of tumor microvascular density and branch formation. Markedly, the vasculature in PlGF-expressing tumors consisted of relatively large-diameter microvessels with substantial improvement of pericyte coverage. Similarly, PlGF-induced vascular normalization and remodeling were also observed in a spontaneous human choriocarcinoma that expressed endogenous PlGF. Our findings shed light on functions of PlGF as a vascular remodeling factor that normalizes the tumor vasculature and thus may have conceptual implications of cancer therapy.
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| 4. |
- Hosaka, K, et al.
(författare)
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Dual roles of endothelial FGF-2-FGFR1-PDGF-BB and perivascular FGF-2-FGFR2-PDGFRβ signaling pathways in tumor vascular remodeling
- 2018
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Ingår i: Cell discovery. - : Springer Science and Business Media LLC. - 2056-5968. ; 4, s. 3-
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Tidskriftsartikel (refereegranskat)abstract
- Perivascular cells are important cellular components in the tumor microenvironment (TME) and they modulate vascular integrity, remodeling, stability, and functions. Here we show using mice models that FGF-2 is a potent pericyte-stimulating factor in tumors. Mechanistically, FGF-2 binds to FGFR2 to stimulate pericyte proliferation and orchestrates the PDGFRβ signaling for vascular recruitment. FGF-2 sensitizes the PDGFRβ signaling through increasing PDGFRβ levels in pericytes. To ensure activation of PDGFRβ, the FGF-2–FGFR1-siganling induces PDGF-BB and PDGF-DD, two ligands for PDGFRβ, in angiogenic endothelial cells. Thus, FGF-2 directly and indirectly stimulates pericyte proliferation and recruitment by modulating the PDGF–PDGFRβ signaling. Our study identifies a novel mechanism by which the FGF-2 and PDGF-BB collaboratively modulate perivascular cell coverage in tumor vessels, thus providing mechanistic insights of pericyte–endothelial cell interactions in TME and conceptual implications for treatment of cancers and other diseases by targeting the FGF-2–FGFR-pericyte axis.
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| 5. |
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| 6. |
- Hosaka, K, et al.
(författare)
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Therapeutic paradigm of dual targeting VEGF and PDGF for effectively treating FGF-2 off-target tumors
- 2020
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 3704-
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Tidskriftsartikel (refereegranskat)abstract
- FGF-2 displays multifarious functions in regulation of angiogenesis and vascular remodeling. However, effective drugs for treating FGF-2+ tumors are unavailable. Here we show that FGF-2 modulates tumor vessels by recruiting NG2+ pricytes onto tumor microvessels through a PDGFRβ-dependent mechanism. FGF-2+ tumors are intrinsically resistant to clinically available drugs targeting VEGF and PDGF. Surprisingly, dual targeting the VEGF and PDGF signaling produces a superior antitumor effect in FGF-2+ breast cancer and fibrosarcoma models. Mechanistically, inhibition of PDGFRβ ablates FGF-2-recruited perivascular coverage, exposing anti-VEGF agents to inhibit vascular sprouting. These findings show that the off-target FGF-2 is a resistant biomarker for anti-VEGF and anti-PDGF monotherapy, but a highly beneficial marker for combination therapy. Our data shed light on mechanistic interactions between various angiogenic and remodeling factors in tumor neovascularization. Optimization of antiangiogenic drugs with different principles could produce therapeutic benefits for treating their resistant off-target cancers.
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| 7. |
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| 8. |
- Jing, X, et al.
(författare)
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COVID-19 instigates adipose browning and atrophy through VEGF in small mammals
- 2022
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Ingår i: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:12, s. 1674-
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Tidskriftsartikel (refereegranskat)abstract
- Patients with COVID-19 frequently manifest adipose atrophy, weight loss and cachexia, which significantly contribute to poor quality of life and mortality1,2. Browning of white adipose tissue and activation of brown adipose tissue are effective processes for energy expenditure3–7; however, mechanistic and functional links between SARS-CoV-2 infection and adipose thermogenesis have not been studied. In this study, we provide experimental evidence that SARS-CoV-2 infection augments adipose browning and non-shivering thermogenesis (NST), which contributes to adipose atrophy and body weight loss. In mouse and hamster models, SARS-CoV-2 infection activates brown adipose tissue and instigates a browning or beige phenotype of white adipose tissues, including augmented NST. This browning phenotype was also observed in post-mortem adipose tissue of four patients who died of COVID-19. Mechanistically, high levels of vascular endothelial growth factor (VEGF) in the adipose tissue induces adipose browning through vasculature–adipocyte interaction. Inhibition of VEGF blocks COVID-19-induced adipose tissue browning and NST and partially prevents infection-induced body weight loss. Our data suggest that the browning of adipose tissues induced by COVID-19 can contribute to adipose tissue atrophy and weight loss observed during infection. Inhibition of VEGF signaling may represent an effective approach for preventing and treating COVID-19-associated weight loss.
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| 9. |
- Seki, T, et al.
(författare)
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Ablation of endothelial VEGFR1 improves metabolic dysfunction by inducing adipose tissue browning
- 2018
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Ingår i: The Journal of experimental medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 215:2, s. 611-626
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Tidskriftsartikel (refereegranskat)abstract
- Angiogenesis plays an instrumental role in the modulation of adipose tissue mass and metabolism. Targeting adipose vasculature provides an outstanding opportunity for treatment of obesity and metabolic disorders. Here, we report the physiological functions of VEGFR1 in the modulation of adipose angiogenesis, obesity, and global metabolism. Pharmacological inhibition and genetic deletion of endothelial VEGFR1 augmented adipose angiogenesis and browning of subcutaneous white adipose tissue, leading to elevated thermogenesis. In a diet-induced obesity model, endothelial-VEGFR1 deficiency demonstrated a potent anti-obesity effect by improving global metabolism. Along with metabolic changes, fatty liver and insulin sensitivity were also markedly improved in VEGFR1-deficient high fat diet (HFD)–fed mice. Together, our data indicate that targeting of VEGFR1 provides an exciting new opportunity for treatment of obesity and metabolic diseases, such as liver steatosis and type 2 diabetes.
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| 10. |
- Seki, T, et al.
(författare)
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Brown-fat-mediated tumour suppression by cold-altered global metabolism
- 2022
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 608:7922, s. 421-
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Tidskriftsartikel (refereegranskat)abstract
- Glucose uptake is essential for cancer glycolysis and is involved in non-shivering thermogenesis of adipose tissues1–6. Most cancers use glycolysis to harness energy for their infinite growth, invasion and metastasis2,7,8. Activation of thermogenic metabolism in brown adipose tissue (BAT) by cold and drugs instigates blood glucose uptake in adipocytes4,5,9. However, the functional effects of the global metabolic changes associated with BAT activation on tumour growth are unclear. Here we show that exposure of tumour-bearing mice to cold conditions markedly inhibits the growth of various types of solid tumours, including clinically untreatable cancers such as pancreatic cancers. Mechanistically, cold-induced BAT activation substantially decreases blood glucose and impedes the glycolysis-based metabolism in cancer cells. The removal of BAT and feeding on a high-glucose diet under cold exposure restore tumour growth, and genetic deletion of Ucp1—the key mediator for BAT-thermogenesis—ablates the cold-triggered anticancer effect. In a pilot human study, mild cold exposure activates a substantial amount of BAT in both healthy humans and a patient with cancer with mitigated glucose uptake in the tumour tissue. These findings provide a previously undescribed concept and paradigm for cancer therapy that uses a simple and effective approach. We anticipate that cold exposure and activation of BAT through any other approach, such as drugs and devices either alone or in combination with other anticancer therapeutics, will provide a general approach for the effective treatment of various cancers.
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