Prolonged fasting drives a program of metabolic inflammation in human adipose tissue
Objective: The human adaptive fasting response enables survival during periods of caloric deprivation. A crucial component of the fasting response is the shift from glucose metabolism to utilization of lipids, underscoring the importance of adipose tissue as the central lipid-storing organ. The obje...
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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/S2212877820301563 |
| _version_ | 1818590446622867456 |
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| author | Pouneh K. Fazeli Yang Zhang John O'Keefe Tristan Pesaresi Mingyue Lun Brian Lawney Matthew L. Steinhauser |
| author_facet | Pouneh K. Fazeli Yang Zhang John O'Keefe Tristan Pesaresi Mingyue Lun Brian Lawney Matthew L. Steinhauser |
| author_sort | Pouneh K. Fazeli |
| collection | DOAJ |
| description | Objective: The human adaptive fasting response enables survival during periods of caloric deprivation. A crucial component of the fasting response is the shift from glucose metabolism to utilization of lipids, underscoring the importance of adipose tissue as the central lipid-storing organ. The objective of this study was to investigate the response of adipose tissue to a prolonged fast in humans. Methods: We performed RNA sequencing of subcutaneous adipose tissue samples longitudinally collected during a 10-day, 0-calorie fast in humans. We further investigated observed transcriptional signatures utilizing cultured human monocytes and Thp1 cells. We examined the cellularity of adipose tissue biopsies with transmission electron microscopy and tested for associated changes in relevant inflammatory mediators in the systemic circulation by ELISA assays of longitudinally collected blood samples. Results: Coincident with the expected shift away from glucose utilization and lipid storage, we demonstrated downregulation of pathways related to glycolysis, oxidative phosphorylation, and lipogenesis. The canonical lipolysis pathway was also downregulated, whereas fasting drove alternative lysosomal paths to lipid digestion. Unexpectedly, the dominant induced pathways were associated with immunity and inflammation, although this only became evident at the 10-day time point. Among the most augmented transcripts were those associated with macrophage identity and function, such as members of the erythroblast transformation-specific (ETS) transcription factor family. Key components of the macrophage transcriptional signal in fasting adipose tissue were recapitulated with induced expression of two of the ETS transcription factors via cultured macrophages, SPIC and SPI1. The inflammatory signal was further reflected by an increase in systemic inflammatory mediators. Conclusions: Collectively, this study demonstrates an unexpected role of metabolic inflammation in the human adaptive fasting response. |
| first_indexed | 2024-12-16T09:56:40Z |
| format | Article |
| id | doaj.art-eea256eefcbb4ae38c4dc685cec26e37 |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-16T09:56:40Z |
| publishDate | 2020-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-eea256eefcbb4ae38c4dc685cec26e372022-12-21T22:35:55ZengElsevierMolecular Metabolism2212-87782020-12-0142101082Prolonged fasting drives a program of metabolic inflammation in human adipose tissuePouneh K. Fazeli0Yang Zhang1John O'Keefe2Tristan Pesaresi3Mingyue Lun4Brian Lawney5Matthew L. Steinhauser6Department of Medicine, Neuroendocrine Unit, Massachusetts General Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA; Department of Medicine, Division of Endocrinology, Neuroendocrinology Unit, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Center for Human Integrative Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Corresponding author. 200 Lothrop Street, BST W1061, University of Pittsburgh School of Medicine, Pittsburgh PA, 15213, USA.Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USACenter for Human Integrative Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USADepartment of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USAQuantitative Biomedical Research Center, Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USAHarvard Medical School, Boston, MA, USA; Center for Human Integrative Physiology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA, USA; Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA; Corresponding author. 100 Technology Drive, Bridgeside Point 558, Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh PA, 15219, USA.Objective: The human adaptive fasting response enables survival during periods of caloric deprivation. A crucial component of the fasting response is the shift from glucose metabolism to utilization of lipids, underscoring the importance of adipose tissue as the central lipid-storing organ. The objective of this study was to investigate the response of adipose tissue to a prolonged fast in humans. Methods: We performed RNA sequencing of subcutaneous adipose tissue samples longitudinally collected during a 10-day, 0-calorie fast in humans. We further investigated observed transcriptional signatures utilizing cultured human monocytes and Thp1 cells. We examined the cellularity of adipose tissue biopsies with transmission electron microscopy and tested for associated changes in relevant inflammatory mediators in the systemic circulation by ELISA assays of longitudinally collected blood samples. Results: Coincident with the expected shift away from glucose utilization and lipid storage, we demonstrated downregulation of pathways related to glycolysis, oxidative phosphorylation, and lipogenesis. The canonical lipolysis pathway was also downregulated, whereas fasting drove alternative lysosomal paths to lipid digestion. Unexpectedly, the dominant induced pathways were associated with immunity and inflammation, although this only became evident at the 10-day time point. Among the most augmented transcripts were those associated with macrophage identity and function, such as members of the erythroblast transformation-specific (ETS) transcription factor family. Key components of the macrophage transcriptional signal in fasting adipose tissue were recapitulated with induced expression of two of the ETS transcription factors via cultured macrophages, SPIC and SPI1. The inflammatory signal was further reflected by an increase in systemic inflammatory mediators. Conclusions: Collectively, this study demonstrates an unexpected role of metabolic inflammation in the human adaptive fasting response.http://www.sciencedirect.com/science/article/pii/S2212877820301563Adipose tissueFastingInflammationMacrophageHumanSPIC |
| spellingShingle | Pouneh K. Fazeli Yang Zhang John O'Keefe Tristan Pesaresi Mingyue Lun Brian Lawney Matthew L. Steinhauser Prolonged fasting drives a program of metabolic inflammation in human adipose tissue Molecular Metabolism Adipose tissue Fasting Inflammation Macrophage Human SPIC |
| title | Prolonged fasting drives a program of metabolic inflammation in human adipose tissue |
| title_full | Prolonged fasting drives a program of metabolic inflammation in human adipose tissue |
| title_fullStr | Prolonged fasting drives a program of metabolic inflammation in human adipose tissue |
| title_full_unstemmed | Prolonged fasting drives a program of metabolic inflammation in human adipose tissue |
| title_short | Prolonged fasting drives a program of metabolic inflammation in human adipose tissue |
| title_sort | prolonged fasting drives a program of metabolic inflammation in human adipose tissue |
| topic | Adipose tissue Fasting Inflammation Macrophage Human SPIC |
| url | http://www.sciencedirect.com/science/article/pii/S2212877820301563 |
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