Insulin Acutely Regulates Gene Expression in Brain–A New Potential Major Level of Control of Metabolism and Neurotransmission

Abstract

While the brain is now recognized as an insulin sensitive tissue, and impaired insulin signaling in brain can lead to many metabolic and behavioral abnormalities, effects of insulin on gene expression in the brain remain largely unknown. To understand now this aspect of insulin action may impact physiology in vivo, we performed hyperinsulinemic-euglycemic clamps at low (4 mU/kg/min) and high (12 mU/kg/min) physiological doses of insulin in C57BL/6 mice, and after 3 hours collected different brain regions and analyzed their transcriptomes using RNA Seq. In response to low dose insulin infusion, 1851 genes were up- or down-regulated in the hypothalamus by at least 50% (all P < 0.01). This was more than 4-fold as the number of genes regulated in liver or muscle under the same conditions. Other regions showed different responses with 2significantly regulated by at least 50% in hippocampus and 131 regulated in nucleus accumbens. The most upregulated pathway in all three regions was that for very long chain fatty acyl-CoA synthesis, indicating an important role of insulin action on brain fatty acid metabolism. Most other insulin responsive genes in these three brain regions were distinct. In the hypothalamus, insulin played a key role in modulating genes involved in neurotransmission in the hypothalamus, including enhancing the GABA-A receptor signaling pathway and suppressing neuropeptide signaling pathways. Insulin also modulated metabolism in the hypothalamus by suppressing the glycolysis and pentose phosphate pathways, while increasing the pyruvate dehydrogenase complex and cholesterol biosynthesis. Thus, insulin action in the brain acutely and potently regulates expression of genes involved in brain metabolism, neurotransmission and neuromodulation. In this way, insulin re-routes the carbon source to the biogenesis of plasma membrane for neuronal and glial function and synaptic remodeling. Disclosure W. Cai: None. A. Ramirez: None. J. Dreyfuss: None. T.M. Batista: None. R. Garcia Martin: None. H. Pan: None. M.E. Li: None. B.T. O'Neill: None. J.K. Kim: None. C. Kahn: Advisory Panel; Self; CohBar, ERX Therapeutics, AntriaBio, Inc.. Board Member; Self; Kaleio Biosciences.