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Peripheral Insulin Regulates a Broad Network of Gene Expression in the Hypothalamus, Hippocampus and Nucleus Accumbens

posted on 25.05.2021, 22:57 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 Kahn
The 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.


This work was supported by NIH grants R37 DK031036, R01 DK033201 (to C.R.K.) and 5U2C-DK093000 (to J.K.K.), and the Mary K. Iacocca Professorship (to C.R.K.). W.C. was supported by NIH grants K01 DK120740 and P30 DK057521; A.K.R. was supported by NIH grant T32 DK007260-37; T.M.B was partially supported by grant from Sao Paulo Research Foundation (2014/25370-8); R.G.M. was supported by a Deutsche Forschungsgemeinschaft (DFG) fellowship; S.S. was supported by NIH grant P30 GM127211 and NASPGHAN Foundation Young Investigator Award. G.W. was supported by ADA postdoc fellowship grant (1-18-PDF-171); B.T.O. was supported by NIH grant K08 DK100543.