Endothelial-specific deficiency of megalin in the brain protects mice against high-fat diet challenge.

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.

• Authors: Fernando Bartolome, Desiree Antequera, Macarena de la Cueva, Marcos Rubio-Fernandez, Nerea Castro, Consuelo Pascual, Antoni Camins, Eva Carro
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 17 Issue 1 Pg. 22 (Jan 14 2020) ISSN: 1742-2094 [Electronic] England
• PMID: 31937343 (Publication Type: Journal Article)

Chemical References

• Low Density Lipoprotein Receptor-Related Protein-2
• Lrp2 protein, mouse

Topics

• Animals
• Blood-Brain Barrier (metabolism)
• Brain (metabolism)
• Diet, High-Fat (adverse effects)
• Endothelium, Vascular (metabolism)
• Energy Metabolism (physiology)
• Low Density Lipoprotein Receptor-Related Protein-2 (metabolism)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Obesity (metabolism)