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Publication
Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus,
Hippocampus, and Nucleus Accumbens.
Authors Cai W, Zhang X, Batista TM, García-Martín R, Softic S, Wang G, Ramirez AK,
Konishi M, O'Neill BT, Kim JH, Kim JK, Kahn CR
Submitted By Submitted Externally on 12/3/2021
Status Published
Journal Diabetes
Year 2021
Date Published 8/1/2021
Volume : Pages 70 : 1857 - 1873
PubMed Reference 34031123
Abstract The brain is now recognized as an insulin-sensitive tissue; however, the role of
changing insulin concentrations in the peripheral circulation in gene expression
in the brain is largely unknown. Here, we performed a
hyperinsulinemic-euglycemic clamp on 3-month-old male C57BL/6 mice for 3 h. We
show that, in comparison with results in saline-infused controls, increases in
peripheral insulin within the physiological range regulate expression of a broad
network of genes in the brain. Insulin regulates distinct pathways in the
hypothalamus (HTM), hippocampus, and nucleus accumbens. Insulin shows its most
robust effect in the HTM and regulates multiple genes involved in
neurotransmission, including upregulating 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 HTM, 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.




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