Regulation of lymphatic function and injury by nitrosative stress in obese mice
Objective: Obesity results in lymphatic dysfunction, but the cellular mechanisms that mediate this effect remain largely unknown. Previous studies in obese mice have shown that inducible nitric oxide synthase-expressing (iNOS+) inflammatory cells accumulate around lymphatic vessels. In the current s...
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| Format: | Article |
| Language: | English |
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Elsevier
2020-12-01
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| Series: | Molecular Metabolism |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877820301551 |
| _version_ | 1818385970577276928 |
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| author | Sonia Rehal Raghu P. Kataru Geoffrey E. Hespe Jung Eun Baik Hyeung Ju Park Catherine Ly JinYeon Shin Babak J. Mehrara |
| author_facet | Sonia Rehal Raghu P. Kataru Geoffrey E. Hespe Jung Eun Baik Hyeung Ju Park Catherine Ly JinYeon Shin Babak J. Mehrara |
| author_sort | Sonia Rehal |
| collection | DOAJ |
| description | Objective: Obesity results in lymphatic dysfunction, but the cellular mechanisms that mediate this effect remain largely unknown. Previous studies in obese mice have shown that inducible nitric oxide synthase-expressing (iNOS+) inflammatory cells accumulate around lymphatic vessels. In the current study, we therefore tested the hypothesis that increased expression of iNOS results in nitrosative stress and injury to the lymphatic endothelial cells (LECs). In addition, we tested the hypothesis that lymphatic injury, independent of obesity, can modulate glucose and lipid metabolism. Methods: We compared the metabolic changes and lymphatic function of wild-type and iNOS knockout mice fed a normal chow or high-fat diet for 16 weeks. To corroborate our in vivo findings, we analyzed the effects of reactive nitrogen species on isolated LECs. Finally, using a genetically engineered mouse model that allows partial ablation of the lymphatic system, we studied the effects of acute lymphatic injury on glucose and lipid metabolism in lean mice. Results: The mesenteric lymphatic vessels of obese wild-type animals were dilated, leaky, and surrounded by iNOS+ inflammatory cells with resulting increased accumulation of reactive nitrogen species when compared with lean wild-type or obese iNOS knockout animals. These changes in obese wild-type mice were associated with systemic glucose and lipid abnormalities, as well as decreased mesenteric LEC expression of lymphatic-specific genes, including vascular endothelial growth factor receptor 3 (VEGFR-3) and antioxidant genes as compared with lean wild-type or obese iNOS knockout animals. In vitro experiments demonstrated that isolated LECs were more sensitive to reactive nitrogen species than blood endothelial cells, and that this sensitivity was ameliorated by antioxidant therapies. Finally, using mice in which the lymphatics were specifically ablated using diphtheria toxin, we found that the interaction between metabolic abnormalities caused by obesity and lymphatic dysfunction is bidirectional. Targeted partial ablation of mesenteric lymphatic channels of lean mice resulted in increased accumulation of iNOS+ inflammatory cells and increased reactive nitrogen species. Lymphatic ablation also caused marked abnormalities in insulin sensitivity, serum glucose and insulin concentrations, expression of insulin-sensitive genes, lipid metabolism, and significantly increased systemic and mesenteric white adipose tissue (M-WAT) inflammatory responses. Conclusions: Our studies suggest that increased iNOS production in obese animals plays a key role in regulating lymphatic injury by increasing nitrosative stress. In addition, our studies suggest that obesity-induced lymphatic injury may amplify metabolic abnormalities by increasing systemic and local inflammatory responses and regulating insulin sensitivity. These findings suggest that manipulation of the lymphatic system may represent a novel means of treating metabolic abnormalities associated with obesity. |
| first_indexed | 2024-12-14T03:46:37Z |
| format | Article |
| id | doaj.art-d2e62f3bd0704c459e4d4119803f4a61 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-14T03:46:37Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-d2e62f3bd0704c459e4d4119803f4a612022-12-21T23:18:20ZengElsevierMolecular Metabolism2212-87782020-12-0142101081Regulation of lymphatic function and injury by nitrosative stress in obese miceSonia Rehal0Raghu P. Kataru1Geoffrey E. Hespe2Jung Eun Baik3Hyeung Ju Park4Catherine Ly5JinYeon Shin6Babak J. Mehrara7Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USAPlastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USAPlastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USAPlastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USAPlastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USAPlastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USAPlastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USACorresponding author. Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Suite MRI 1005, New York, NY, 10065, USA.; Plastic and Reconstructive Surgery Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USAObjective: Obesity results in lymphatic dysfunction, but the cellular mechanisms that mediate this effect remain largely unknown. Previous studies in obese mice have shown that inducible nitric oxide synthase-expressing (iNOS+) inflammatory cells accumulate around lymphatic vessels. In the current study, we therefore tested the hypothesis that increased expression of iNOS results in nitrosative stress and injury to the lymphatic endothelial cells (LECs). In addition, we tested the hypothesis that lymphatic injury, independent of obesity, can modulate glucose and lipid metabolism. Methods: We compared the metabolic changes and lymphatic function of wild-type and iNOS knockout mice fed a normal chow or high-fat diet for 16 weeks. To corroborate our in vivo findings, we analyzed the effects of reactive nitrogen species on isolated LECs. Finally, using a genetically engineered mouse model that allows partial ablation of the lymphatic system, we studied the effects of acute lymphatic injury on glucose and lipid metabolism in lean mice. Results: The mesenteric lymphatic vessels of obese wild-type animals were dilated, leaky, and surrounded by iNOS+ inflammatory cells with resulting increased accumulation of reactive nitrogen species when compared with lean wild-type or obese iNOS knockout animals. These changes in obese wild-type mice were associated with systemic glucose and lipid abnormalities, as well as decreased mesenteric LEC expression of lymphatic-specific genes, including vascular endothelial growth factor receptor 3 (VEGFR-3) and antioxidant genes as compared with lean wild-type or obese iNOS knockout animals. In vitro experiments demonstrated that isolated LECs were more sensitive to reactive nitrogen species than blood endothelial cells, and that this sensitivity was ameliorated by antioxidant therapies. Finally, using mice in which the lymphatics were specifically ablated using diphtheria toxin, we found that the interaction between metabolic abnormalities caused by obesity and lymphatic dysfunction is bidirectional. Targeted partial ablation of mesenteric lymphatic channels of lean mice resulted in increased accumulation of iNOS+ inflammatory cells and increased reactive nitrogen species. Lymphatic ablation also caused marked abnormalities in insulin sensitivity, serum glucose and insulin concentrations, expression of insulin-sensitive genes, lipid metabolism, and significantly increased systemic and mesenteric white adipose tissue (M-WAT) inflammatory responses. Conclusions: Our studies suggest that increased iNOS production in obese animals plays a key role in regulating lymphatic injury by increasing nitrosative stress. In addition, our studies suggest that obesity-induced lymphatic injury may amplify metabolic abnormalities by increasing systemic and local inflammatory responses and regulating insulin sensitivity. These findings suggest that manipulation of the lymphatic system may represent a novel means of treating metabolic abnormalities associated with obesity.http://www.sciencedirect.com/science/article/pii/S2212877820301551ObesityLymphatic functioniNOSNitrosative stressMetabolismInflammation |
| spellingShingle | Sonia Rehal Raghu P. Kataru Geoffrey E. Hespe Jung Eun Baik Hyeung Ju Park Catherine Ly JinYeon Shin Babak J. Mehrara Regulation of lymphatic function and injury by nitrosative stress in obese mice Molecular Metabolism Obesity Lymphatic function iNOS Nitrosative stress Metabolism Inflammation |
| title | Regulation of lymphatic function and injury by nitrosative stress in obese mice |
| title_full | Regulation of lymphatic function and injury by nitrosative stress in obese mice |
| title_fullStr | Regulation of lymphatic function and injury by nitrosative stress in obese mice |
| title_full_unstemmed | Regulation of lymphatic function and injury by nitrosative stress in obese mice |
| title_short | Regulation of lymphatic function and injury by nitrosative stress in obese mice |
| title_sort | regulation of lymphatic function and injury by nitrosative stress in obese mice |
| topic | Obesity Lymphatic function iNOS Nitrosative stress Metabolism Inflammation |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820301551 |
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