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Calcineurin A beta deficiency ameliorates HFD-induced hypothalamic astrocytosis in mice

Pfuhlmann, Katrin, Schriever, Sonja C., Legutko, Beata, Baumann, Peter, Harrison, Luke, Kabra, Dhiraj G., Baumgart, Emily Violette, Tschöp, Matthias H., Garcia-Caceres, Cristina, Pfluger, Paul T.·2018·Journal of Neuroinflammation
DOI 10.1186/s12974-018-1076-xPMC PMC5806488
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Fig. 1 Body weight, body composition, and blood glucose of WT and Pppcb KO mice. Subgroups of WT and Ppp3cb KO mice matched for body weight (a), fat mass (b), lean mass (c), and blood glucose levels after 5 h of fasting (d) were selected from a larger cohort of WT and Ppp3cb KO mice that were exposed to HFD for 16 weeks. The selected Ppp3cb KO mice nevertheless showed a decreased body weight gain over the period of HFD feeding when compared to their selected WT controls (e). n = 6. Means ± SEM. Student’s t test: *p < 0.05
Fig. 1 Body weight, body composition, and blood glucose of WT and Pppcb KO mice. Subgroups of WT and Ppp3cb KO mice matched for body weight (a), fat mass (b), lean mass (c), and blood glucose levels after 5 h of fasting (d) were selected from a larger cohort of WT and Ppp3cb KO mice that were exposed to HFD for 16 weeks. The selected Ppp3cb KO mice nevertheless showed a decreased body weight gain over the period of HFD feeding when compared to their selected WT controls (e). n = 6. Means ± SEM. Student’s t test: *p < 0.05CC BY · PubMed Central
Fig. 2 Ppp3cb deficiency is associated with a decrease in GFAP-positive cells in the ARC, DMH, and VMH of HFD-fed mice. Immunohistochemical stainings for GFAP in the arcuate nucleus (ARC), dorsomedial hypothalamus (DMH), and ventromedial hypothalamus (VMH) of HFD-fed Ppp3cb WT and KO mice. Representative images of the mediobasal hypothalamus (a, b, upper pictures) and of astrocytes in the ARC, VMH, DMH (a, b, lower pictures) of HFD-fed Ppp3cb WT, and KO mice. Numbers of GFAP-positive cells in the ARC (c), VMH (d), and DMH (e). Length of primary projections in the ARC of Ppp3cb WT and KO mice (f). Numbers of primary projection per astrocyte in the ARC (g), VMH (h), and DMH (i). Means ± SEM; n = 6 biological replicates per genotype (four pictures per biological replicate were quantified) except for (d), where only five KO brains could be used and (f) where length could be measured only in four KO brains; unpaired two-tailed Student’s t test. *p < 0.05, **p < 0.01
Fig. 2 Ppp3cb deficiency is associated with a decrease in GFAP-positive cells in the ARC, DMH, and VMH of HFD-fed mice. Immunohistochemical stainings for GFAP in the arcuate nucleus (ARC), dorsomedial hypothalamus (DMH), and ventromedial hypothalamus (VMH) of HFD-fed Ppp3cb WT and KO mice. Representative images of the mediobasal hypothalamus (a, b, upper pictures) and of astrocytes in the ARC, VMH, DMH (a, b, lower pictures) of HFD-fed Ppp3cb WT, and KO mice. Numbers of GFAP-positive cells in the ARC (c), VMH (d), and DMH (e). Length of primary projections in the ARC of Ppp3cb WT and KO mice (f). Numbers of primary projection per astrocyte in the ARC (g), VMH (h), and DMH (i). Means ± SEM; n = 6 biological replicates per genotype (four pictures per biological replicate were quantified) except for (d), where only five KO brains could be used and (f) where length could be measured only in four KO brains; unpaired two-tailed Student’s t test. *p < 0.05, **p < 0.01CC BY · PubMed Central
Fig. 3 Ppp3cb deficiency decreases the number of Iba1 positive cells in the VMH of HFD-fed mice. Immunohistochemical staining for Iba1 in the ARC, DMH, and VMH of Ppp3cb WT (a) and KO (b) mice and quantitative analysis of Iba1-positive microglia (c–e) in the ARC (c), VMH (d), and DMH (e). Means ± SEM; n = 6 WT and five KO mice (c), n = 6 mice per genotype (d, e); n = 4 pictures per biological replicate were quantified. Unpaired two-tailed Student’s t test. **p < 0.01
Fig. 3 Ppp3cb deficiency decreases the number of Iba1 positive cells in the VMH of HFD-fed mice. Immunohistochemical staining for Iba1 in the ARC, DMH, and VMH of Ppp3cb WT (a) and KO (b) mice and quantitative analysis of Iba1-positive microglia (c–e) in the ARC (c), VMH (d), and DMH (e). Means ± SEM; n = 6 WT and five KO mice (c), n = 6 mice per genotype (d, e); n = 4 pictures per biological replicate were quantified. Unpaired two-tailed Student’s t test. **p < 0.01CC BY · PubMed Central
Fig. 4 Pharmacological inhibition of calcineurin decreases GFAP fluorescence intensity in the ARC of mice acutely exposed to HFD. WT mice on chow (a, b) and HFD (c, d) were treated with 1 mg/kg/day of calcineurin inhibitor Fk506 for 1 week; HFD feeding was started in parallel. Fk506 treatment resulted in a significant reduction in body weight in mice on chow (a) and HFD (c), while no significant changes in body composition on chow (b) and HFD (d) were detected. GFAP (e, f) and IBA1 (g, h) staining in the ARC, VMH, and DMH of vehicle and Fk506-treated WT mice on HFD (scale 200 μm) revealed a decrease in GFAP fluorescence intensity in the ARC (e, f) Real-time qPCRs of mice on chow and HFD (i–m) were performed for Gfap and Iba1 (i), inflammatory cytokines (j), Cd169 as marker for monocyte infiltration (k), calcineurin subunits (l), and calcineurin downstream targets (m). Means ± SEM; n = 6 biological replicates (a, b); n = 10 biological replicates, except for lean mass vehicle, where one value was identified as a significant outlier (c, d); n = 4 biological replicates (f, g); n = 6 biological replicates, except for Gfap chow vehicle, where one value was identified as a significant outlier (i–m)
Fig. 4 Pharmacological inhibition of calcineurin decreases GFAP fluorescence intensity in the ARC of mice acutely exposed to HFD. WT mice on chow (a, b) and HFD (c, d) were treated with 1 mg/kg/day of calcineurin inhibitor Fk506 for 1 week; HFD feeding was started in parallel. Fk506 treatment resulted in a significant reduction in body weight in mice on chow (a) and HFD (c), while no significant changes in body composition on chow (b) and HFD (d) were detected. GFAP (e, f) and IBA1 (g, h) staining in the ARC, VMH, and DMH of vehicle and Fk506-treated WT mice on HFD (scale 200 μm) revealed a decrease in GFAP fluorescence intensity in the ARC (e, f) Real-time qPCRs of mice on chow and HFD (i–m) were performed for Gfap and Iba1 (i), inflammatory cytokines (j), Cd169 as marker for monocyte infiltration (k), calcineurin subunits (l), and calcineurin downstream targets (m). Means ± SEM; n = 6 biological replicates (a, b); n = 10 biological replicates, except for lean mass vehicle, where one value was identified as a significant outlier (c, d); n = 4 biological replicates (f, g); n = 6 biological replicates, except for Gfap chow vehicle, where one value was identified as a significant outlier (i–m)CC BY · PubMed Central

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Metadata

Authors
Pfuhlmann, K., Schriever, S. C., Legutko, B., Baumann, P., Harrison, L., Kabra, D. G., Baumgart, E. V., Tschöp, M. H., Garcia-Caceres, C., & Pfluger, P. T.
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2018-02-08
Volume
15
Issue
1
ISSN
1742-2094
DOI
10.1186/s12974-018-1076-x
PMC
PMC5806488
Cited by
9
References
3
Language
en
Funders
  • Helmholtz-Gemeinschaft (Portfolio Program Metabolic Dysfunction, ICEMED 'Imaging and Curing Environmental Metabolic Diseases' Alliance, Helmholtz-Israel-Cooperation in Personalized Medicine, Personalized Medicine Initiative, Initiative and Networking Fund)
  • Alexander von Humboldt-Stiftung

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