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

Autor(es):Mostrar menos -

Cai, Weikang ^{[1, 2]} ; Zhang, Xuemei ^[1] ; Batista, Thiago M. ^[1] ; Garcia-Martin, Ruben ^[1] ; Softic, Samir ^{[1, 3]} ; Wang, Guoxiao ^[1] ; Ramirez, Alfred K. ^[1] ; Konishi, Masahiro ^[1] ; O'Neill, Brian T. ^{[4, 1]} ; Kim, Jong Hun ^{[5, 6]} ; Kim, Jason K. ^{[5, 7]} ; Kahn, C. Ronald ^[1]

Afiliação do(s) autor(es)

^[1] Harvard Med Sch, Joslin Diabet Ctr, Sect Integrat Physiol & Metab, Boston, MA 02115 - USA

^[2] New York Inst Technol, Coll Osteopath Med, Dept Biomed Sci, Old Westbury, NY 11568 - USA

^[3] Univ Kentucky, Coll Med, Dept Pediat, Lexington, KY - USA

^[4] Univ Iowa, Carver Coll Med, Fraternal Order Eagles Diabet Res Ctr, Div Endocrinol & Metab, Iowa City, IA - USA

^[5] Univ Massachusetts, Med Sch, Dept Med, Program Mol Med, Worcester, MA 01605 - USA

^[6] Sungshin Univ, Dept Food Sci & Biotechnol, Seoul - South Korea

^[7] Univ Massachusetts, Med Sch, Dept Med, Div Endocrinol Metab & Diabet, Worcester, MA 01605 - USA

• Tipo de documento: Artigo Científico
• Fonte: Diabetes; v. 70, n. 8, p. 1857-1873, AUG 2021.
• Citações Web of Science: 1

Resumo

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. (AU)

• Processo FAPESP: 14/25370-8 - Caracterização de hepatócitos derivados de células tronco pluripotentes induzidas (iPSC) humanas de indivíduos resistentes a insulina
• Beneficiário: Thiago Martins Batista
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Pós-Doutorado