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Endothelial-specific Deficiency of Megalin in the Brain Protects Mice Against High-Fat Diet Challenge

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Endothelial-specific Deficiency of Megalin in the Brain Protects Mice Against High-Fat Diet Challenge

Fernando Bartolome et al. J Neuroinflammation.

Abstract

Background: The increasing risk of obesity and diabetes among other metabolic disorders are the consequence of shifts in dietary patterns with high caloric-content food intake. We previously reported that megalin regulates energy homeostasis using blood-brain barrier (BBB) endothelial megalin-deficient (EMD) mice, since these animals developed obesity and metabolic syndrome upon normal chow diet administration. Obesity in mid-life appears to be related to greater dementia risk and represents an increasing global health issue. We demonstrated that EMD phenotype induced impaired learning ability and recognition memory, neurodegeneration, neuroinflammation, reduced neurogenesis, and mitochondrial deregulation associated with higher mitochondrial mass in cortical tissues.

Methods: EMD mice were subjected to normal chow and high-fat diet (HFD) for 14 weeks and metabolic changes were evaluated.

Results: Surprisingly, BBB megalin deficiency protected against HFD-induced obesity improving glucose tolerance and preventing hepatic steatosis. Compared to wild type (wt), the brain cortex in EMD mice showed increased levels of the mitochondrial biogenesis regulator, peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), and uncoupling protein 2 (UCP2), a thermogenic protein involved in the regulation of energy metabolism. This agreed with the previously found increased mitochondrial mass in the transgenic mice. Upon HFD challenge, we demonstrated these two proteins were found elevated in wt mice but reported no changes over the already increased levels in EMD animals.

Conclusion: We propose a protective role for megalin on diet-induce obesity, suggesting this could be related to metabolic disturbances found in dementia through brain endocrine system communications.

Keywords: High-fat diet; Leptin; Megalin; Mitochondrial biogenesis; Obesity.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
EMD mice display a significant reduction in HFD-induced obesity phenotype. Wt and EMD male mice were fed with NCD or HFD for 14 weeks. a Under NCD, bodyweight gain during 14-week feeding was significantly increased in EMD mice compared to wt. HFD administration significantly increased body weight in both mice groups but this increase was much more significant in wt group (n = 9, in all animal groups). b Fat weight in NCD-fed or HFD-fed mice at week 14. c Glucose tolerance test in wt and EMD mice fed with NCD or HFD for 14 weeks in the 16-h-fasted state (wt NCD, n = 5; wt HFD, n = 6; EMD NCD, n = 8; EMD HFD n = 9). d Scatter plots with bars represent the area under the glucose curve from the glucose tolerance test. e Insulin tolerance test in wt and EMD mice fed with NCD or HFD for 14 weeks in the 6-h-fasted state (wt NCD, n = 5; wt HFD, n = 6; EMD NCD, n = 8; EMD HFD n = 9). f Scatter plots with bars represent the area under the glucose curve from the insulin tolerance test. All data are presented as the mean ± SEM. Statistical significance in a, c and e is based on multivariate ANOVA analysis followed by Games-Howell post hoc test. Statistical significance in b, d, and f was based on one-way ANOVA followed by Games-Howell’s (b and d) or Tukey’s (f) post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001
Fig. 2
Fig. 2
Serum metabolic parameters in wt and EMD mice under NCD and HFD for 14 weeks. (a–f) a Triglycerides (TG), b high-density lipoprotein (HDL), c cholesterol, d non-esterified fatty acid (NEFA), e leptin, and f insulin tests in wt and EMD mice fed with NCD or HFD for 14 weeks. All data are presented as the mean ± SEM. Statistical significance was based on one-way ANOVA followed by Games-Howell’s (a, c, d, and f) or Tukey’s (b and e) post hoc test. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001
Fig. 3
Fig. 3
EMD mice are protected against HFD-induced hepatic steatosis. a Representative images of Oil Red O and H&E co-stained liver sections from NCD and HFD-fed wt and EMD mice. Arrows indicate lipidic stained droplets. Scale bar: 50 μm. b Scatter plots with bars showing the quantification of intracellular fat drops followed by Oil Red O staining. c Liver weight in NCD or HFD-fed mice at week 20. All data are presented as the mean ± SEM. Statistical significance was based on one-way ANOVA followed by Games-Howell’s post hoc test. *P < 0.05, **P < 0.01
Fig. 4
Fig. 4
HFD challenge does not affect the PGC1-1α and UCP2 cortex levels in EMD mice. (a–c) a Protein levels of Complex V-β subunit (CxVβ), b PGC-1α, and c UCP-2 were significantly higher in EMD mice cortical samples compared to samples from the same brain area in wt animals under NCD. HFD administration increased b PGC-1α, and c UCP-2 protein levels in wt mice but not in EMD mice. Scatter plots with bars represent the quantification of protein expression in each animal group, and representative western blots are shown (right panels). All data represent the mean of at least 3 independent experiments ±SEM. Statistical significance was based on the Kruskal-Wallis ANOVA test (a) or one-way ANOVA (b and c) followed by Games-Howell’s post hoc test (b and c). *P < 0.05, **P < 0.01
Fig. 5
Fig. 5
Glial activation markers in wt and EMD mice under NCD and HFD for 14 weeks. (a–c) a Protein levels of GFAP, and b Iba1 were significantly higher in HFD-fed wt mice compared to NCD fed animals. Upon NCD, GFAP expression was also significantly increased in EMD mice compared to wt mice. a, b Scatter plots with bars represent protein levels quantification in each animal group. c Representative western blots are shown. All data are presented as the mean ± SEM. Statistical significance was based on one-way ANOVA test followed by Games-Howell’s post hoc test (b and c). *P < 0.05

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