Diabetes and Insulin in Regulation of Brain Cholesterol Metabolism

SummaryThe brain is the most cholesterol-rich organ in the body, most of which comes from in situ synthesis. Here we demonstrate that in insulin-deficient diabetic mice, there is a reduction in expression of the major transcriptional regulator of cholesterol metabolism, SREBP-2, and its downstream genes in the hypothalamus and other areas of the brain, leading to a reduction in brain cholesterol synthesis and synaptosomal cholesterol content. These changes are due, at least in part, to direct effects of insulin to regulate these genes in neurons and glial cells and can be corrected by intracerebroventricular injections of insulin. Knockdown of SREBP-2 in cultured neurons causes a decrease in markers of synapse formation and reduction of SREBP-2 in the hypothalamus of mice using shRNA results in increased feeding and weight gain. Thus, insulin and diabetes can alter brain cholesterol metabolism, and this may play an important role in the neurologic and metabolic dysfunction observed in diabetes and other disease states.

Graphical AbstractFigure optionsDownload high-quality image (169 K)Download as PowerPoint slideHighlights
► SREBP-2 and cholesterol biosynthesis are decreased in brain in diabetes
► This results in reduced cholesterol content in synaptosomal membrane
► Insulin directly activates SREBP-2 pathway in brain, both in vivo and in vitro
► Reduced SREBP-2 in neurons affects synapses and regulation of feeding behavior