Journal article
Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus, Hippocampus, and Nucleus Accumbens
Diabetes (New York, N.Y.), Vol.70(8), pp.1857-1873
08/2021
DOI: 10.2337/db20-1119
PMCID: PMC8385615
PMID: 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.
Details
- Title: Subtitle
- Peripheral Insulin Regulates a Broad Network of Gene Expression in Hypothalamus, Hippocampus, and Nucleus Accumbens
- Creators
- Weikang Cai - Joslin Diabetes CenterXuemei Zhang - Joslin Diabetes CenterThiago M Batista - Joslin Diabetes CenterRubén García-Martín - Joslin Diabetes CenterSamir Softic - University of KentuckyGuoxiao Wang - Joslin Diabetes CenterAlfred K Ramirez - Joslin Diabetes CenterMasahiro Konishi - Joslin Diabetes CenterBrian T O'Neill - University of IowaJong Hun Kim - Sungshin Women's UniversityJason K Kim - University of Massachusetts Chan Medical SchoolC Ronald Kahn - Joslin Diabetes Center
- Resource Type
- Journal article
- Publication Details
- Diabetes (New York, N.Y.), Vol.70(8), pp.1857-1873
- DOI
- 10.2337/db20-1119
- PMID
- 34031123
- PMCID
- PMC8385615
- NLM abbreviation
- Diabetes
- ISSN
- 1939-327X
- eISSN
- 1939-327X
- Grant note
- R01 DK031036 / NIDDK NIH HHS K01 DK120740 / NIDDK NIH HHS P20 GM103527 / NIGMS NIH HHS R01 MH125903 / NIMH NIH HHS P30 DK057521 / NIDDK NIH HHS P30 GM127211 / NIGMS NIH HHS P30 DK036836 / NIDDK NIH HHS R01 DK033201 / NIDDK NIH HHS K08 DK100543 / NIDDK NIH HHS R01 DK128429 / NIDDK NIH HHS T32 DK007260 / NIDDK NIH HHS R37 DK031036 / NIDDK NIH HHS P30 DK054759 / NIDDK NIH HHS U24 DK093000 / NIDDK NIH HHS
- Language
- English
- Date published
- 08/2021
- Academic Unit
- Endocrinology and Metabolism; Internal Medicine
- Record Identifier
- 9984359904402771
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