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Impaired insulin signaling in brain leads to both metabolic and behavioral abnormalities. To understand the role of insulin on gene expression in the brain, we performed hyperinsulinemic-euglycemic clamps using physiological doses of insulin in C57BL/6 mice, and after 3 hours collected different brain regions and analyzed their transcriptomes by RNA Seq. In response to peripheral insulin, 1851 genes were up-or down-regulated in the hypothalamus by at least 50%(all P< 0.01). Other regions showed different responses with 205 genes significantly regulated by≥ 50% in hippocampus and 131 regulated in nucleus accumbens. Insulin upregulated the pathway for very long chain fatty acyl-CoA synthesis in all three regions, but most insulin responsive genes were region specific. Thus, in hypothalamus, insulin modulated metabolism by suppressing the glycolysis and pentose phosphate pathway, while increasing …