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Peripheral Insulin Regulates a Broad Network of Gene Expression in the Hypothalamus, Hippocampus and Nucleus Accumbens
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posted on 2021-05-25, 22:57 authored by Weikang Cai, Xuemei Zhang, Thiago M. Batista, Rubén García-Martín, Samir Softic, Guoxiao Wang, Alfred K. Ramirez, Masahiro Konishi, Brian T. O’Neill, Jong Hun Kim, Jason K. Kim, C. Ronald KahnThe brain is now recognized as an insulin
sensitive tissue, however, the role of changing insulin concentrations in the
peripheral circulation on gene expression in the brain is largely unknown. Here
we perform hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice
for 3 hours. We show that increases in peripheral insulin within the
physiological range regulate expression of a broad network of gene expression
in the brain compared with saline-infused controls. Insulin regulates distinct
pathways in the hypothalamus, hippocampus and nucleus accumbens. Insulin shows its
most robust effect in the hypothalamus and regulates multiple genes involved in
neurotransmission, including up-regulating expression of multiple subunits of
GABA-A receptors, Na+ and K+ channels, and SNARE proteins;
differentially modulating glutamate receptors; and suppressing multiple
neuropeptides. Insulin also strongly modulates metabolic genes in the
hypothalamus, suppressing genes in the glycolysis and pentose phosphate
pathways, while increasing expression of genes regulating pyruvate
dehydrogenase and long-chain fatty acyl-CoA and cholesterol biosynthesis,
thereby rerouting of carbon substrates from glucose metabolism to lipid
metabolism required for the biogenesis of membranes for neuronal and glial
function and synaptic remodeling. Furthermore, based on the transcriptional
signatures, these changes in gene expression involve neurons, astrocytes,
oligodendrocytes, microglia and endothelial cells. Thus, peripheral insulin
acutely and potently regulates expression of a broad network of genes involved
in neurotransmission and brain metabolism. Dysregulation of these pathways
could have dramatic effects in normal physiology and diabetes.