Liver and White/Brown Fat Dystrophy Associates with Gut Microbiota and Metabolomic Alterations in 3xTg Alzheimer’s Disease Mouse Model
Abstract
:1. Introduction
2. Results
2.1. Glucose Metabolism
2.2. Tissue Lipid Content
2.3. Liver Inflammation
2.4. Circulating Markers
2.5. Effect of Intranasal Insulin Therapy in 3xTg HFD Mice
2.6. Serum and Fecal Metabolome
2.7. Gut Microbial Profile
3. Discussion
4. Materials and Methods
4.1. Study Design
4.2. PET-CT Scanning and Image Processing
4.3. Liver Histology
4.4. Adipose Tissues Histology
4.5. BAT UCP1 Protein Expression
4.6. Biochemical Analyses
4.7. Gut Microbiota Profile by 16S rRNA Amplicon Sequencing
4.8. Serum and Fecal Metabolites by 1H-NMR Spectroscopy
4.9. Statistical Analysis
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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n (for Each Group) | WT-ND | WT-HFD | 3xTg-ND | 3xTg-HFD | 3xTg-HFD-INI | |
---|---|---|---|---|---|---|
8 months | ||||||
Body weight (g) | 9-9-8-7-11 | 41.2 ± 1.4 | 47.4 ± 2.7 ^ | 34.5 ± 0.5 *** | 37.4 ± 1.6 **,^ | 30.4 ± 1.2 ###,°° |
Glycaemia (mmol/L) | 7-9-8-7-11 | 4.9 ± 0.4 | 10.4 ± 1.1 ^^^ | 6.7 ± 0.6 | 12.6 ± 1.9 ###,***,^^^ | 7.6 ± 0.3 #,°° |
Triglycerides (mg/dL) | 9-9-8-6-10 | 106 ± 11 | 160 ± 8 ^ | 94 ± 5 | 115 ± 19 | 85 ± 7 # |
ALT (U/L) | 8-9-7-6-10 | 72 ± 28 | 176 ± 37 ^ | 85 ± 16 | 53 ± 3 * | 39 ± 6 |
AST (U/L) | 8-9-8-6-10 | 280 ± 159 | 313 ± 128 | 678 ± 216 * | 667 ± 160 # | 657 ± 155 # |
Leptin (ng/mL) | 8-7-8-7-11 | 4.7 ± 1.3 | 6.9 ± 2.4 | 0.3 ± 0.1 *** | 1.8 ± 0.7 ^^ | 0.9 ± 0.3 ## |
Insulin (ng/mL) | 7-7-8-7-11 | 2.9 ± 1.1 | 4.2 ± 1.2 | 4.1 ± 1.2 | 2.3 ± 0.8 | 1.3 ± 0.2 |
IL-6 (pg/mL) | 9-9-8-6-10 | 124 ± 37 | 114 ± 23 | 63 ± 13 | 62 ± 21 * | 148 ± 37 ° |
MCP-1 (pg/mL) | 9-9-8-7-10 | 40 ± 11 | 37 ± 10 | 16 ± 2 ** | 22 ± 5 * | 41 ± 8 ° |
PAI-1 (ng/mL) | 9-8-6-7-10 | 5.5 ± 1.2 | 6.1 ± 1.4 | 10.0 ± 1.2 * | 17.7 ± 3.9 ###,** | 14.6 ± 3.3 ## |
Resistin (pg/mL) | 9-9-8-7-11 | 278 ± 87 | 346 ± 68 | 180 ± 40 | 374 ± 30 ^ | 382 ± 69 |
14 months | ||||||
Body weight (g) | 10-12-9-6-7 | 51.3 ± 1.9 $ | 58.5 ± 2.6 ^,$ | 38.7 ± 0.8 ***,$ | 51.2 ± 6.8 ^^ | 41.2 ± 3.9 #,°,$ |
Glucose (mmol/L) | 10-12-8-6-7 | 7.4 ± 1.2 | 6.9 ± 0.7 $ | 8.3 ± 0.6 | 7.9 ± 2.2 $ | 11.2 ± 1.4 # |
Triglycerides (md/dL) | 9-11-9-5-7 | 95 ± 9 | 91 ± 6 $ | 73 ± 3 *,$ | 79 ± 6 $ | 87 ± 10 |
ALT (U/L) | 7-11-8-5-6 | 110 ± 28 | 138 ± 25 | 51 ± 10 | 192 ± 98 | 71 ± 13 |
AST (U/L) | 9-11-8-3-7 | 578 ± 133 | 560 ± 131 | 485 ± 92 | 131 ± 25 | 480 ± 88 |
Leptin (ng/mL) | 10-11-9-6-7 | 14.4 ± 2.4 $ | 20.7 ± 3.1 $ | 0.5 ± 0.1 ***,$ | 2.7 ± 0.9 ###,***,^ | 2.3 ± 0.9 ###,$ |
Insulin (ng/mL) | 10-11-9-6-7 | 3.8 ± 0.8 | 10.1 ± 2.2 | 2.9 ± 0.8 | 3.1 ± 1.2 * | 2.5 ± 1.1 |
IL-6 (pg/mL) | 8-10-8-6-7 | 1618 ± 472 | 1247 ± 571 $ | 145 ± 90 *** | 606 ± 318 # | 311 ± 229 ### |
MCP-1 (pg/mL) | 9-10-9-6-7 | 97 ± 22 $ | 71 ± 16 $ | 45 ± 24 * | 35 ± 11 # | 20 ± 2 ## |
PAI-1 (ng/mL) | 10-12-9-5-7 | 9.8 ± 2.4 | 12.6 ± 2.9 | 15.7 ± 3.8 * | 16.8 ± 2.7 | 10.4 ± 2.0 |
Resistin (pg/mL) | 10-12-9-6-7 | 874 ± 244 $ | 957 ± 127 $ | 279 ± 124 * | 854 ± 209 ^^ | 296 ± 58 ° |
8 Months | 14 Months | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
TG (mg/dL) | Leptin (pg/mL) | PAI-1 (pg/mL) | TG (mg/dL) | Leptin (pg/mL) | PAI-1 (pg/mL) | IL6 (pg/mL) | MCP-1 (pg/mL) | Insulin (pg/mL) | Resistin (pg/mL) | |
Liver GE | 0.271 | −0.061 | 0.172 | 0.304 | 0.409 ** | −0.112 | 0.478 ** | 0.471 ** | 0.278 | 0.542 ** |
Liver GU | 0.493 ** | 0.067 | 0.174 | 0.315 * | 0.239 | −0.295 | 0.035 | 0.192 | −0.051 | 0.100 |
Liver radiodensity | −0.436 ** | −0.598 ** | 0.199 | −0.577 ** | −0.885 ** | 0.321 * | −0.420 * | −0.615 ** | −0.507 ** | −0.500 ** |
Liver macrovescicular steatosis | 0.558 ** | 0.496 * | −0.037 | 0.364 | 0.601 ** | −0.505 * | 0.263 | 0.469 * | 0.131 | 0.343 |
Liver total steatosis | 0.550 ** | 0.578 ** | −0.187 | 0.437 * | 0.560 ** | −0.588 ** | 0.050 | 0.080 | 0.008 | 0.189 |
Liver portal inflammation | −0.518 * | −0.433 * | 0.489 * | −0.314 | −0.449 * | 0.347 | −0.260 | −0.386 | −0.497 * | −0.402 |
Liver ballooning | 0.649 ** | 0.405 | −0.285 | 0.008 | 0.363 | −0.272 | 0.214 | 0.398 | 0.212 | 0.333 |
Liver steatoinflammatory score | 0.522 * | 0.590 ** | −0.264 | 0.232 | 0.370 | −0.369 | −0.058 | 0.422 * | −0.048 | 0.185 |
WAT radiodensity | −0.530 ** | −0.536 ** | 0.350 * | −0.516 ** | −0.781 ** | 0.243 | −0.545 ** | −0.604 ** | −0.394 * | −0.436 ** |
WAT cell count | −0.634 ** | −0.700 ** | 0.223 | −0.323 | −0.493 * | 0.579 ** | −0.205 | −0.272 | −0.013 | −0.136 |
BAT radiodensity | −0.603 ** | −0.758 ** | 0.437 ** | −0.582 ** | −0.822 ** | 0.354 * | −0.468 ** | −0.546 ** | −0.506 ** | −0.452 ** |
BAT lipid droplets | 0.622 ** | 0.643 ** | −0.382 | 0.614 ** | 0.647 ** | −0.559 ** | 0.474 * | 0.369 | 0.245 | 0.522 ** |
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Guzzardi, M.A.; La Rosa, F.; Campani, D.; Collado, M.C.; Monleon, D.; Cacciato Insilla, A.; Tripodi, M.; Zega, A.; Dattilo, A.; Brunetto, M.R.; et al. Liver and White/Brown Fat Dystrophy Associates with Gut Microbiota and Metabolomic Alterations in 3xTg Alzheimer’s Disease Mouse Model. Metabolites 2022, 12, 278. https://doi.org/10.3390/metabo12040278
Guzzardi MA, La Rosa F, Campani D, Collado MC, Monleon D, Cacciato Insilla A, Tripodi M, Zega A, Dattilo A, Brunetto MR, et al. Liver and White/Brown Fat Dystrophy Associates with Gut Microbiota and Metabolomic Alterations in 3xTg Alzheimer’s Disease Mouse Model. Metabolites. 2022; 12(4):278. https://doi.org/10.3390/metabo12040278
Chicago/Turabian StyleGuzzardi, Maria Angela, Federica La Rosa, Daniela Campani, Maria Carmen Collado, Daniel Monleon, Andrea Cacciato Insilla, Maria Tripodi, Alessandro Zega, Alessia Dattilo, Maurizia Rossana Brunetto, and et al. 2022. "Liver and White/Brown Fat Dystrophy Associates with Gut Microbiota and Metabolomic Alterations in 3xTg Alzheimer’s Disease Mouse Model" Metabolites 12, no. 4: 278. https://doi.org/10.3390/metabo12040278