| 1. |
- Adermark, Louise, 1974, et al.
(författare)
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Weight gain and neuroadaptations elicited by high fat diet depend on fatty acid composition.
- 2021
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Ingår i: Psychoneuroendocrinology. - : Elsevier BV. - 1873-3360 .- 0306-4530. ; 126
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Tidskriftsartikel (refereegranskat)abstract
- Overconsumption of food is a major health concern in the western world. Palatable food has been shown to alter the activity of neural circuits, and obesity has been linked to alterations in the connectivity between the hypothalamus and cortical regions involved in decision-making and reward processing, putatively modulating the incentive value of food. Outlining neurophysiological adaptations induced by dietary intake of high fat diets (HFD) is thus valuable to establish how the diet by itself may promote overeating. To this end, C57BL/6 mice were fed HFD rich in either saturated fatty acids (HFD-S) or polyunsaturated fatty acids (HFD-P), or a low-fat control diet (LFD) for four weeks. Food and energy intake were monitored and ex vivo electrophysiology was employed to assess neuroadaptations in lateral hypothalamus (LH) and corticostriatal circuits, previously associated with food intake. In addition, the effects of dietary saturated and polyunsaturated fatty acids on the gene expression of NMDA, AMPA and GABAA receptor subunits in the hypothalamus were investigated. Our data shows that mice fed HFD-P had increased daily food and energy intake compared with mice fed HFD-S or LFD. However, this increase in energy intake had no obesogenic effects. Electrophysiological recordings demonstrated that HFD-P had a selective effect on glutamatergic neurotransmission in the LH, which was concomitant with a change in mRNA expression of AMPA receptor subtypes Gria1, Gria3 and Gria4, with no effect on the mRNA expression of NMDA receptor subtypes or GABAA receptor subtypes. Furthermore, while synaptic output from corticostriatal subregions was not significantly modulated by diet, synaptic plasticity in the form of long-term depression (LTD) was impaired in the dorsomedial striatum of mice fed HFD-S. In conclusion, this study suggests that the composition of fatty acids in the diet not only affects weight gain, but may also modulate neuronal function and plasticity in brain regions involved in food intake.
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| 2. |
- Fischer, J., et al.
(författare)
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Leptin signaling impairs macrophage defenses against Salmonella Typhimurium
- 2019
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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. - 0027-8424. ; 116:33, s. 16551-16560
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Tidskriftsartikel (refereegranskat)abstract
- The dynamic interplay between metabolism and immune responses in health and disease, by which different immune cells impact on metabolic processes, are being increasingly appreciated. However, the potential of master regulators of metabolism to control innate immunity are less understood. Here, we studied the cross-talk between leptin signaling and macrophage function in the context of bacterial infections. We found that upon infection with Gram-negative pathogens, such as Salmonella Typhimurium, leptin receptor (Lepr) expression increased in both mouse and human macrophages. Unexpectedly, both genetic Lepr ablation in macrophages and global pharmacologic leptin antagonization augmented lysosomal functions, reduced S. Typhimurium burden, and diminished inflammation in vitro and in vivo. Mechanistically, we show that leptin induction activates the mTORC2/Akt pathway and subsequently down-regulates Phlpp1 phosphatase, allowing for phosphorylated Akt to impair lysosomal-mediated pathogen clearance. These data highlight a link between leptin signaling, the mTORC2/Phlpp1/Akt axis, and lysosomal activity in macrophages and have important therapeutic implications for modulating innate immunity to combat Gram-negative bacterial infections.
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| 3. |
- Gutiérrez, Saray, et al.
(författare)
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Effects of Omega-3 Fatty Acids on Immune Cells.
- 2019
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 20:20
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Forskningsöversikt (refereegranskat)abstract
- Alterations on the immune system caused by omega-3 fatty acids have been described for 30 years. This family of polyunsaturated fatty acids exerts major alterations on the activation of cells from both the innate and the adaptive immune system, although the mechanisms for such regulation are diverse. First, as a constitutive part of the cellular membrane, omega-3 fatty acids can regulate cellular membrane properties, such as membrane fluidity or complex assembly in lipid rafts. In recent years, however, a new role for omega-3 fatty acids and their derivatives as signaling molecules has emerged. In this review, we describe the latest findings describing the effects of omega-3 fatty acids on different cells from the immune system and their possible molecular mechanisms.
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| 4. |
- Mårtensson, Jonas, et al.
(författare)
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The ketone body acetoacetate activates human neutrophils through FFAR2.
- 2023
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Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 1938-3673. ; 113:6, s. 577-587
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils express many surface receptors that sense environmental changes. One such sensor is FFAR2 (free fatty acid receptor 2), a receptor that detects gut microbiota-derived short chain fatty acids. As such, FFAR2 has been regarded as a molecular link between metabolism and inflammation. Our recent studies on FFAR2, using its endogenous agonist propionate in combination with allosteric modulators, have identified several novel aspects of FFAR2 regulation. A recent study has also identified the ketone body acetoacetate as an endogenous ligand for mouse FFAR2. Whether human FFAR2 also recognizes acetoacetate and how this recognition modulates human neutrophil functions has not been earlier investigated. In this study, we found that acetoacetate can induce a decrease of cAMP and translocation of β-arrestin in cells overexpressing FFAR2. In addition, we show that similar to propionate, FFAR2 specific allosteric modulators enhance acetoacetate-induced transient rise in cytosolic calcium, production of reactive oxygen species and cell migration in human neutrophils. In summary, we demonstrate that human neutrophils recognize the ketone body acetoacetate through FFAR2. Thus, our data further highlight the key role of FFAR2 in inflammation and metabolism.
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| 5. |
- Parma, L., et al.
(författare)
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Bis(maltolato)oxovanadium(IV) Induces Angiogenesis via Phosphorylation of VEGFR2
- 2020
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 21:13
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Tidskriftsartikel (refereegranskat)abstract
- VEGFR2 and VEGF-A play a pivotal role in the process of angiogenesis. VEGFR2 activation is regulated by protein tyrosine phosphatases (PTPs), enzymes that dephosphorylate the receptor and reduce angiogenesis. We aim to study the effect of PTPs blockade using bis(maltolato)oxovanadium(IV) (BMOV) on in vivo wound healing and in vitro angiogenesis. BMOV significantly improves in vivo wound closure by 45% in C57BL/6JRj mice. We found that upon VEGFR2 phosphorylation induced by endogenously produced VEGF-A, the addition of BMOV results in increased cell migration (45%), proliferation (40%) and tube formation (27%) in HUVECs compared to control. In a mouse ex vivo, aortic ring assay BMOV increased the number of sprouts by 3 folds when compared to control. However, BMOV coadministered with exogenous VEGF-A increased ECs migration, proliferation and tube formation by only 41%, 18% and 12% respectively and aortic ring sprouting by only 1-fold. We also found that BMOV enhances VEGFR2 Y951 and p38MAPK phosphorylation, but not ERK1/2. The level of phosphorylation of these residues was the same in the groups treated with BMOV supplemented with exogenous VEGF-A and exogenous VEGF-A only. Our study demonstrates that BMOV is able to enhance wound closure in vivo. Moreover, in the presence of endogenous VEGF-A, BMOV is able to stimulate in vitro angiogenesis by increasing the phosphorylation of VEGFR2 and its downstream proangiogenic enzymes. Importantly, BMOV had a stronger proangiogenic effect compared to its effect in coadministration with exogenous VEGF-A.
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| 6. |
- Svahn, Sara L, et al.
(författare)
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Dietary Polyunsaturated Fatty Acids Promote Neutrophil Accumulation in the Spleen by Altering Chemotaxis and Delaying Cell Death
- 2019
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Ingår i: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 87:8
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils are the most abundant circulating leukocytes in humans and are essential for the defense against invading pathogens. Like many other cells of an organism, neutrophils can be highly influenced by the diet. We have previously described that mice fed a high-fat diet rich in polyunsaturated fatty acids (HFD-P) present a higher frequency of neutrophils in bone marrow than mice fed a high-fat diet rich in saturated fatty acids (HFD-S). Interestingly, such an increase correlated with improved survival against bacterium-induced sepsis. In this study, we aimed to investigate the effects of dietary polyunsaturated and saturated fatty acids on neutrophil homeostasis. We found that HFD-P specifically induced the accumulation of neutrophils in the marginal pools of the spleen and liver. The accumulation of neutrophils in the spleen was a result of a dual effect of polyunsaturated fatty acids on neutrophil homeostasis. First, polyunsaturated fatty acids enhanced the recruitment of neutrophils from the circulation into the spleen via chemokine secretion. Second, they delayed neutrophil cell death in the spleen. Interestingly, these effects were not observed in mice fed a diet rich in saturated fatty acids, suggesting that the type of fat rather than the amount of fat mediates the alterations in neutrophil homeostasis. In conclusion, our results show that dietary polyunsaturated fatty acids have a strong modulatory effect on neutrophil homeostasis that may have future clinical applications.
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| 7. |
- Svahn, Sara L., et al.
(författare)
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Dietary Polyunsaturated Fatty Acids Promote Neutrophil Accumulation in the Spleen by Altering Chemotaxis and Delaying Cell Death
- 2019
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Ingår i: Infection and Immunity. - 1098-5522 .- 0019-9567. ; 87:8
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Tidskriftsartikel (refereegranskat)abstract
- Neutrophils are the most abundant circulating leukocytes in humans and are essential for the defense against invading pathogens. Like many other cells of an organism, neutrophils can be highly influenced by the diet. We have previously described that mice fed a high-fat diet rich in polyunsaturated fatty acids (HFD-P) present a higher frequency of neutrophils in bone marrow than mice fed a high-fat diet rich in saturated fatty acids (HFD-S). Interestingly, such an increase correlated with improved survival against bacterium-induced sepsis. In this study, we aimed to investigate the effects of dietary polyunsaturated and saturated fatty acids on neutrophil homeostasis. We found that HFD-P specifically induced the accumulation of neutrophils in the marginal pools of the spleen and liver. The accumulation of neutrophils in the spleen was a result of a dual effect of polyunsaturated fatty acids on neutrophil homeostasis. First, polyunsaturated fatty acids enhanced the recruitment of neutrophils from the circulation into the spleen via chemokine secretion. Second, they delayed neutrophil cell death in the spleen. Interestingly, these effects were not observed in mice fed a diet rich in saturated fatty acids, suggesting that the type of fat rather than the amount of fat mediates the alterations in neutrophil homeostasis. In conclusion, our results show that dietary polyunsaturated fatty acids have a strong modulatory effect on neutrophil homeostasis that may have future clinical applications.
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| 8. |
- Svahn, Sara L, et al.
(författare)
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Spleen proteomics data from high fat diet fed mice
- 2020
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Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 32
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Tidskriftsartikel (refereegranskat)abstract
- The composition of the diet affects many processes in the body, including body weight and endocrine system. We have previously shown that dietary fat also affects the immune system. Mice fed high fat diet rich in polyunsaturated fatty acids survive S. aureus infection to a much greater extent than mice fed high fat diet rich in saturated fatty acids. Here we present data regarding the dietary effects on protein expression in spleen from mice fed three different diets, I) low fat/chow diet (LFD, n = 4), II) high fat diet rich in saturated fatty acids (HFD-S, n = 4) and III) high fat diet rich in polyunsaturated fatty acids (HFD-P, n = 4). We performed mass spectrophotometry based quantitative proteomics analysis of isolated spleen by implementing the isobaric tags for relative and absolute quantification (iTRAQ) approach. Mass spectrometry data were analyzed using Proteome Discoverer 2.4 software using the search engine mascot against Mus musculus in SwissProt. 924 proteins are identified in all sets (n = 4) for different dietary effects taken for statistical analysis using Qlucore Omics Explorer software. Only 20 proteins were found to be differentially expressed with a cut-off value of false discovery rate < 0.1 (q-value) when comparing HFD-S and HFD-P but no differentially expressed proteins were found when LFD was compared with HFD-P or HFD-S. The identified proteins and statistical analysis comparing HFD-S and HFD-P diets are available as a supplementary file S1. We identified a subset of proteins that showed an inverse expression pattern between two high fat diets. These differentially expressed proteins were further classified by gene ontology for their role in biological processes and molecular functions. Mass spectrometry raw data are also available via ProteomeXchange with identifier PXD020365.
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| 9. |
- Ulleryd, Marcus A, et al.
(författare)
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RNA sequencing data describing transcriptional changes in aorta of ApoE-/mice after alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) stimulation
- 2020
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Ingår i: Data in Brief. - : Elsevier BV. - 2352-3409. ; 30
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Tidskriftsartikel (refereegranskat)abstract
- This manuscript is a companion paper to Ulleryd M.U. et al., "Stimulation of alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells" Atherosclerosis, 2019 [1]. Data shown here include RNA sequencing data from whole aorta of ApoE-/- mice fed high fat diet and treated with the alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR) agonist AZ6983 for 8 weeks using subcutaneously implanted osmotic minipumps. Here we present the top gene networks affected by treatment with AZ6983, as well as the up- and down-regulated genes in aorta after treatment. Further, a URL link to the RNA sequencing datasets submitted to GEO is included. (C) 2020 The Authors. Published by Elsevier Inc.
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| 10. |
- Ulleryd, Marcus A, et al.
(författare)
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Stimulation of alpha 7 nicotinic acetylcholine receptor (α7nAChR) inhibits atherosclerosis via immunomodulatory effects on myeloid cells.
- 2019
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Ingår i: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 287, s. 122-133
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Tidskriftsartikel (refereegranskat)abstract
- Alpha 7 nicotinic acetylcholine receptor (α7nAChR) stimulation can regulate acute inflammation, and lack of α7nAChR accelerates atherosclerosis in mice. In this study, we aimed to investigate the effects of the novel α7nAChR agonist, AZ6983, on atherosclerosis and assess its possible immunomodulating effects.AZ6983 was tested in vitro in LPS-challenged mouse and human blood and in vivo using the acute inflammatory air pouch model. Thereafter, long-term effects of AZ6983 treatment on atherosclerosis and immune responses were assessed in apoE-/- mice after 8 and 12 weeks. Atherosclerosis was investigated in the aortic root and thoracic aorta, serum levels of cytokines were analysed and RNAseq was used to study aortic gene expression. Further, bone-marrow-derived macrophages were used to assess phagocytosis in vitro.α7nAChR activation by AZ6983 decreased pro-inflammatory cytokines in acute stimulations of human and mouse blood in vitro, as well as in vivo using the air pouch model. Treating apoE-/- mice with AZ6983 decreased atherosclerosis by 37-49% and decreased serum cytokine levels. RNAseq analysis of aortae suggested the involvement of several specific myeloid cell functions, including phagocytosis. In line with this, AZ6983 significantly increased phagocytosis in bone marrow-derived macrophages.This study demonstrates that activation of α7nAChR with AZ6983 inhibits atherosclerosis in apoE-/-mice and that immunomodulating effects on myeloid cells, such as enhanced phagocytosis and suppression of inflammatory cytokines, could be part of the athero-protective mechanisms. The observed anti-inflammatory effect in human blood supports the idea that AZ6983 may decrease disease also in humans.
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