Editors' ChoiceDiabetes

Insulin Resistance Results in Brain Drain

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Science Translational Medicine  22 Dec 2010:
Vol. 2, Issue 63, pp. 63ec198
DOI: 10.1126/scitranslmed.3002059

Cholesterol is critical for many basic processes in the brain, such as myelin production. Indeed, several hereditary central nervous system diseases are caused by or linked to impaired cholesterol metabolism, including Niemann-Pick disease and Alzheimer’s disease. Although the brain contains more cholesterol than any other organ in the body, the blood-brain barrier prevents cholesterol uptake from the circulation. Therefore, cholesterol must be synthesized de novo in the brain, which consequently produces the complete enzymatic machinery required for cholesterol production as well as the master transcription factor SRBEB-2, which regulates the expression of these enzymes.

Evidence from epidemiological studies in humans and from animal models suggests that insulin resistance, in particular brain insulin resistance, contributes to the pathogenesis of Alzheimer’s disease. Suzuki et al. now describe how insulin regulates brain cholesterol metabolism, which provides a link between insulin resistance and neurological dysfunction.

The authors first showed in microarray studies that hypothalami from type 1 diabetic (insulin-deficient) mice expressed reduced levels of cholesterologenic genes and that nuclear (active) SREBP-2 expression was decreased. This decrease in gene expression was found to have functional significance because the in vivo cholesterol synthesis rate was decreased in the brains of these diabetic mice. Although total cholesterol levels were not different, the cholesterol content of isolated synaptosomal membranes was lower. These alterations in cholesterol levels were not due to hyperglycemia but instead to the insulin deficiency in this diabetes mouse model. Moreover, SREBP-2 inhibition with a lentiviral shSREBP-2 in primary mouse hippocampal neurons resulted in a 40% reduction in the density of synapse formation on the neurites as well as a decrease in the staining intensity of the synaptic vesicle marker VAMP2—evidence of a role of cholesterol in synaptic vesicle biogenesis and exocytosis. Thus, dysregulation of brain cholesterol metabolism because of impaired brain insulin action may provide a novel mechanism of altered brain and neuronal function, which could represent a mechanistic link between insulin resistance, aging, and neurodegenerative disorders such as Alzheimer’s.

R. Suzuki et al., Diabetes and insulin in regulation of brain cholesterol metabolism. Cell Metab. 12, 567–579 (2010). [Abstract]

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