Article ; Online: Myeloid cell-specific disruption of Period1 and Period2 exacerbates diet-induced inflammation and insulin resistance.
The Journal of biological chemistry
2014 Volume 289, Issue 23, Page(s) 16374–16388
Abstract: ... inflammation, and systemic insulin resistance. Our results demonstrate that 1) macrophages from high fat diet ... into wild-type mice potentiates high fat diet-induced adipose and liver tissue inflammation and systemic ... proinflammatory activation, 2) global disruption of the clock genes Period1 (Per1) and Per2 recapitulates ...
| Abstract | The circadian clockworks gate macrophage inflammatory responses. Given the association between clock dysregulation and metabolic disorders, we conducted experiments to determine the extent to which over-nutrition modulates macrophage clock function and whether macrophage circadian dysregulation is a key factor linking over-nutrition to macrophage proinflammatory activation, adipose tissue inflammation, and systemic insulin resistance. Our results demonstrate that 1) macrophages from high fat diet-fed mice are marked by dysregulation of the molecular clockworks in conjunction with increased proinflammatory activation, 2) global disruption of the clock genes Period1 (Per1) and Per2 recapitulates this amplified macrophage proinflammatory activation, 3) adoptive transfer of Per1/2-disrupted bone marrow cells into wild-type mice potentiates high fat diet-induced adipose and liver tissue inflammation and systemic insulin resistance, and 4) Per1/2-disrupted macrophages similarly exacerbate inflammatory responses and decrease insulin sensitivity in co-cultured adipocytes in vitro. Furthermore, PPARγ levels are decreased in Per1/2-disrupted macrophages and PPARγ2 overexpression ameliorates Per1/2 disruption-associated macrophage proinflammatory activation, suggesting that this transcription factor may link the molecular clockworks to signaling pathways regulating macrophage polarization. Thus, macrophage circadian clock dysregulation is a key process in the physiological cascade by which diet-induced obesity triggers macrophage proinflammatory activation, adipose tissue inflammation, and insulin resistance. |
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| MeSH term(s) | Adipocytes/metabolism ; Animals ; Bone Marrow Cells/metabolism ; Coculture Techniques ; Diet, High-Fat ; Inflammation/metabolism ; Insulin Resistance ; Macrophages/metabolism ; Mice ; Mice, Inbred C57BL ; PPAR gamma/metabolism ; Period Circadian Proteins/metabolism | |||||
| Chemical Substances | PPAR gamma ; Per1 protein, mouse ; Per2 protein, mouse ; Period Circadian Proteins | |||||
| Language | English | |||||
| Publishing date | 2014-04-25 | |||||
| Publishing country | United States | |||||
| Document type | Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't | |||||
| ZDB-ID | 2997-x | |||||
| ISSN | 1083-351X ; 0021-9258 | |||||
| ISSN (online) | 1083-351X | |||||
| ISSN | 0021-9258 | |||||
| DOI | 10.1074/jbc.M113.539601 | |||||
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| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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