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Visceral adipose tissue imparts peripheral macrophage influx into the hypothalamus

Chen, Kuan-Hui Ethan, Lainez, Nancy M., Nair, Meera G., Coss, Djurdjica·2021·Journal of Neuroinflammation
DOI 10.1186/s12974-021-02183-2PMC PMC8218389
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Abstract

Background: Obesity is characterized by a systemic inflammation and hypothalamic neuroinflammation. Systemic inflammation is caused by macrophages that infiltrate obese adipose tissues. We previously demonstrated that high-fat diet (HFD)-fed male mice exhibited peripheral macrophage infiltration into the hypothalamus, in addition to activation of resident microglia. Since this infiltration contributes to neuroinflammation and neuronal impairment, herein we characterize the phenotype and origin of these hypothalamic macrophages in HFD mice. Methods: C57BL/6J mice were fed HFD (60% kcal from fat) or control diet with matching sucrose levels, for 12–16 weeks. Males and females were analyzed separately to determine sex-specific responses to HFD. Differences in hypothalamic gene expression in HFD-fed male and female mice, compared to their lean controls, in two different areas of the hypothalamus, were determined using the NanoString neuroinflammation panel. Phenotypic changes in macrophages that infiltrated the hypothalamus in HFD-fed mice were determined by analyzing cell surface markers using flow cytometry and compared to changes in macrophages from the adipose tissue and peritoneal cavity. Adipose tissue transplantation was performed to determine the source of hypothalamic macrophages. Results: We determined that hypothalamic gene expression profiles demonstrate sex-specific and region-specific diet-induced changes. Sex-specific changes included larger changes in males, while region-specific changes included larger changes in the area surrounding the median eminence. Several genes were identified that may provide partial protection to female mice. We also identified diet-induced changes in macrophage migration into the hypothalamus, adipose tissue, and peritoneal cavity, specifically in males. Further, we determined that hypothalamus-infiltrating macrophages express pro-inflammatory markers and markers of metabolically activated macrophages that were identical to markers of adipose tissue macrophages in HFD-fed mice. Employing adipose tissue transplant, we demonstrate that hypothalamic macrophages can originate from the visceral adipose tissue. Conclusion: HFD-fed males experience higher neuroinflammation than females, likely because they accumulate more visceral fat, which provides a source of pro-inflammatory macrophages that migrate to other tissues, including the hypothalamus. Our findings may explain the male bias for neuroinflammation and the metabolic syndrome. Together, our results demonstrate a new connection between the adipose tissue and the hypothalamus in obesity that contributes to neuroinflammation and hypothalamic pathologies.

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Fig. 1 NanoString analysis demonstrates significant changes in gene expression with HFD. Male and female mice were fed control (Ctr) or high fat diet (HFD) for 14 weeks. A Hypothalami from 3 mice per group were dissected and the area containing the arcuate nucleus, and the median eminence from the 300-um coronal section was excised and 50 ng RNA used in NanoString analysis. Genes exhibiting significant changes in expression are highlighted with heat-maps. B The anterior portion containing POA and OVLT was excised and used in a separate NanoString neuroinflammation panel. Genes exhibiting significant changes in expression are listed
Fig. 1 NanoString analysis demonstrates significant changes in gene expression with HFD. Male and female mice were fed control (Ctr) or high fat diet (HFD) for 14 weeks. A Hypothalami from 3 mice per group were dissected and the area containing the arcuate nucleus, and the median eminence from the 300-um coronal section was excised and 50 ng RNA used in NanoString analysis. Genes exhibiting significant changes in expression are highlighted with heat-maps. B The anterior portion containing POA and OVLT was excised and used in a separate NanoString neuroinflammation panel. Genes exhibiting significant changes in expression are listedCC BY · PubMed Central
Fig. 2 Gene expression profile indicates neuroinflammatory changed in mice fed HFD. A A custom panel of 30 genes critical for hypothalamic function was included and several genes highlighted. B, C Highly regulated genes from the 770 gene off-the-shelf neuroinflammation panel are highlighted from the posterior sections (B) and anterior sections (C). The panel contains 7 housekeeping genes used for normalization and 8 genes to determine lower limit. The data analysis was performed using nSolver Analysis Software 4.0 and nCounter Advanced Analysis. Data were plotted as log fold change on x-axis vs. log p value on y-axis. Red indicates genes that increase with HFD compared to control fed mice, while green indicates genes that decease with HFD compared to controls
Fig. 2 Gene expression profile indicates neuroinflammatory changed in mice fed HFD. A A custom panel of 30 genes critical for hypothalamic function was included and several genes highlighted. B, C Highly regulated genes from the 770 gene off-the-shelf neuroinflammation panel are highlighted from the posterior sections (B) and anterior sections (C). The panel contains 7 housekeeping genes used for normalization and 8 genes to determine lower limit. The data analysis was performed using nSolver Analysis Software 4.0 and nCounter Advanced Analysis. Data were plotted as log fold change on x-axis vs. log p value on y-axis. Red indicates genes that increase with HFD compared to control fed mice, while green indicates genes that decease with HFD compared to controlsCC BY · PubMed Central
Fig. 3 Flow cytometry analyses of the hypothalamus (A, B, E), visceral fat pad (C, F), and peritoneal cavity (PEC, D, G) demonstrated macrophage migration following HFD. E An example of flow cytometry gating, indicating the presence of the CD45high macrophage population that can be distinguished from the CD45low microglia specifically in the hypothalami of HFD male mice, but not in female mice. These populations were quantified and presented as the % of all live cells in A (macrophages, CD11b+CD45high) and B (microglia, CD11b+Cd45low). C Quantification of F4/80+CD11b+ macrophages in the stromal vascular fraction of visceral adipose tissue following Ctr and HFD in males (left) and females (right). F An example of the flow cytometry gating strategy from visceral fat. D, G Peritoneal cavity (PEC) cells were analyzed by flow cytometry (gating example G) and the percent of F4/80+CD11b+ macrophages of all live cells are presented graphically in D, males on the left and females on the right. n=9–12 total, 3 repeats consisting of 3–4 mice per group. Statistical significance (*) between Ctr (gray bars) and HFD (black bars) were determined by Student’s T test followed by Tukey’s post hoc test
Fig. 3 Flow cytometry analyses of the hypothalamus (A, B, E), visceral fat pad (C, F), and peritoneal cavity (PEC, D, G) demonstrated macrophage migration following HFD. E An example of flow cytometry gating, indicating the presence of the CD45high macrophage population that can be distinguished from the CD45low microglia specifically in the hypothalami of HFD male mice, but not in female mice. These populations were quantified and presented as the % of all live cells in A (macrophages, CD11b+CD45high) and B (microglia, CD11b+Cd45low). C Quantification of F4/80+CD11b+ macrophages in the stromal vascular fraction of visceral adipose tissue following Ctr and HFD in males (left) and females (right). F An example of the flow cytometry gating strategy from visceral fat. D, G Peritoneal cavity (PEC) cells were analyzed by flow cytometry (gating example G) and the percent of F4/80+CD11b+ macrophages of all live cells are presented graphically in D, males on the left and females on the right. n=9–12 total, 3 repeats consisting of 3–4 mice per group. Statistical significance (*) between Ctr (gray bars) and HFD (black bars) were determined by Student’s T test followed by Tukey’s post hoc testCC BY · PubMed Central
Fig. 4 Peripheral macrophages that increase in the hypothalamus following HFD express pro-inflammatory markers. A The percent of hypothalamic macrophages defined as CD11b+CD45high that express M2-like marker CD206, M1-like pro-inflammatory marker CD11c+PDL1+, and the marker of adipose tissue, metabolically activated, macrophages (ATM) CD11c+CD36+. Bar graphs present the % of all live cells, while pie charts present their proportion of only macrophages. B, C Visceral fat depot (B) or PEC (C) macrophages defined as F4/80+CD11b+ that contain CD206+, or CD11c+PDL1+, or CD11c+CD36+. Bar graphs represent the % of macrophages with these markers of all live cells, while pie charts present the macrophage populations only. n=9–12 per group. Statistical significance (*) between Ctr (gray bars) and HFD (black bars) were determined by Student’s T test followed by Tukey’s post hoc test
Fig. 4 Peripheral macrophages that increase in the hypothalamus following HFD express pro-inflammatory markers. A The percent of hypothalamic macrophages defined as CD11b+CD45high that express M2-like marker CD206, M1-like pro-inflammatory marker CD11c+PDL1+, and the marker of adipose tissue, metabolically activated, macrophages (ATM) CD11c+CD36+. Bar graphs present the % of all live cells, while pie charts present their proportion of only macrophages. B, C Visceral fat depot (B) or PEC (C) macrophages defined as F4/80+CD11b+ that contain CD206+, or CD11c+PDL1+, or CD11c+CD36+. Bar graphs represent the % of macrophages with these markers of all live cells, while pie charts present the macrophage populations only. n=9–12 per group. Statistical significance (*) between Ctr (gray bars) and HFD (black bars) were determined by Student’s T test followed by Tukey’s post hoc testCC BY · PubMed Central
Fig. 5 Chemokine receptor levels. A, C, E, and G The proportion of macrophages (A, E, G)/microglia (C) that express CCR2, CCR5, or CXCR4 receptors. B, D, F, and H Mean fluorescent intensity (MFI) indicates the levels of expression of CCR2, CCR5, or CXCR4 in macrophages. A, B Hypothalamic macrophages CD11b+CD45high; C, D hypothalamic microglia CD11b+CD45low; E, F visceral fat macrophages F4/80+CD11b+; G, H Peritoneal cavity (PEC) macrophages F4/80+CD11b+. The proportion of CCR2-positive cells increases in the hypothalamic macrophages and microglia, while the proportion of CCR5+ macrophages increases in the adipose tissue. PEC macrophages increase proportions of CCR2-, CCR5-, and CXCR4-positive cells. Statistical significance (*) between Ctr (gray bars,) and HFD (black bars) were determined by Student’s T test followed by Tukey’s post hoc test
Fig. 5 Chemokine receptor levels. A, C, E, and G The proportion of macrophages (A, E, G)/microglia (C) that express CCR2, CCR5, or CXCR4 receptors. B, D, F, and H Mean fluorescent intensity (MFI) indicates the levels of expression of CCR2, CCR5, or CXCR4 in macrophages. A, B Hypothalamic macrophages CD11b+CD45high; C, D hypothalamic microglia CD11b+CD45low; E, F visceral fat macrophages F4/80+CD11b+; G, H Peritoneal cavity (PEC) macrophages F4/80+CD11b+. The proportion of CCR2-positive cells increases in the hypothalamic macrophages and microglia, while the proportion of CCR5+ macrophages increases in the adipose tissue. PEC macrophages increase proportions of CCR2-, CCR5-, and CXCR4-positive cells. Statistical significance (*) between Ctr (gray bars,) and HFD (black bars) were determined by Student’s T test followed by Tukey’s post hoc testCC BY · PubMed Central
Fig. 6 Fat transplant. A Experimental design: CD45.2 mice were fed control (Ctr) or high fat diet (HFD) for 12 weeks. Their visceral fat depots were transplanted into visceral depots of 8-week-old recipient CD45.1 mice that were then placed on either Ctr or HFD for additional 7 weeks. The column on the right indicates n in each group and the name of the group, where the first letter indicates the diet of the donor mouse and the second letter shows the diet of the recipient mouse. B Visceral fat depot that contains donor adipose tissue (donor) and recipient adipose tissue (endogenous). Left, H&E stain to observe histology. Right side, immunofluorescent staining using CD31 (green) and DAPI (blue) to detect endothelial cells and demonstrate vascularization of transplanted tissue in the bottom panels compared to the endogenous tissue in the top panels (enlarged areas indicated with squares). C Body weight, visceral fat depot weight, and subcutaneous fat depot weight. Statistically significant difference (*) between control-fed recipient (second letter C) and HFD-fed recipient (second letter H) were determined by ANOVA followed by Tukey’s pos thoc test
Fig. 6 Fat transplant. A Experimental design: CD45.2 mice were fed control (Ctr) or high fat diet (HFD) for 12 weeks. Their visceral fat depots were transplanted into visceral depots of 8-week-old recipient CD45.1 mice that were then placed on either Ctr or HFD for additional 7 weeks. The column on the right indicates n in each group and the name of the group, where the first letter indicates the diet of the donor mouse and the second letter shows the diet of the recipient mouse. B Visceral fat depot that contains donor adipose tissue (donor) and recipient adipose tissue (endogenous). Left, H&E stain to observe histology. Right side, immunofluorescent staining using CD31 (green) and DAPI (blue) to detect endothelial cells and demonstrate vascularization of transplanted tissue in the bottom panels compared to the endogenous tissue in the top panels (enlarged areas indicated with squares). C Body weight, visceral fat depot weight, and subcutaneous fat depot weight. Statistically significant difference (*) between control-fed recipient (second letter C) and HFD-fed recipient (second letter H) were determined by ANOVA followed by Tukey’s pos thoc testCC BY · PubMed Central
Fig. 7 Macrophages migrate from visceral fat pad to the hypothalamus. A Visceral fat pads that contained both donor and endogenous tissue show increase in macrophage percentage following HFD compared to control diet, regardless of donor diet. B Subcutaneous fat depot only contains recipient endogenous CD45.1, indicating that macrophages do not infiltrate subcutaneous fat depot. C Hypothalamus demonstrates increase in macrophage proportion following HFD (left panel), presence of endogenous, recipient CD45.1 (middle panel) and donor CD45.2 macrophages (right panel). D Proportion of pro-inflammatory CD11c+ macrophages and resident CD206+ macrophages within CD45.1 and CD45.2 hypothalamic macrophages. Statistical significance (*) between control-fed recipient (second letter C) and HFD-fed recipient (second letter H) were determined by ANOVA followed by Tukey’s post hoc test
Fig. 7 Macrophages migrate from visceral fat pad to the hypothalamus. A Visceral fat pads that contained both donor and endogenous tissue show increase in macrophage percentage following HFD compared to control diet, regardless of donor diet. B Subcutaneous fat depot only contains recipient endogenous CD45.1, indicating that macrophages do not infiltrate subcutaneous fat depot. C Hypothalamus demonstrates increase in macrophage proportion following HFD (left panel), presence of endogenous, recipient CD45.1 (middle panel) and donor CD45.2 macrophages (right panel). D Proportion of pro-inflammatory CD11c+ macrophages and resident CD206+ macrophages within CD45.1 and CD45.2 hypothalamic macrophages. Statistical significance (*) between control-fed recipient (second letter C) and HFD-fed recipient (second letter H) were determined by ANOVA followed by Tukey’s post hoc testCC BY · PubMed Central

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Sorted by citations

Metadata

Authors
Chen, K.-H. E., Lainez, N. M., Nair, M. G., & Coss, D.
ORCID
Coss, Djurdjica
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2021-06-21
Volume
18
Issue
1
ISSN
1742-2094
DOI
10.1186/s12974-021-02183-2
PMC
PMC8218389
Cited by
38
References
13
Language
en
Licence
Funders
National Institutes of Health (HD091167 NICHD, AI153195)

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

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