Hypoglycemia-activated Hypothalamic Microglia Impairs Glucose Counterregulatory Responses

• Published in: Scientific reports Vol. 9; no. 1; p. 6224
• Main Authors: Winkler, Zsuzsanna, Kuti, Dániel, Polyák, Ágnes, Juhász, Balázs, Gulyás, Krisztina, Lénárt, Nikolett, Dénes, Ádám, Ferenczi, Szilamér, Kovács, Krisztina J.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17-04-2019; Nature Publishing Group
• Subjects: 13/51; 14; 14/1; 14/19; 38; 38/32; 38/77; 631/378/2596/1953; 631/443/319/367/1562; 64; 64/110; 64/60; Agouti-Related Protein - metabolism; Animals; Apposition; Arcuate nucleus; Arcuate Nucleus of Hypothalamus - metabolism; Blood glucose; Blood Glucose - metabolism; Central nervous system; CX3CR1 protein; Fasting; Fractalkine; Glucose; Homeostasis; Homeostasis - genetics; Humanities and Social Sciences; Hypoglycemia; Hypoglycemia - chemically induced; Hypoglycemia - metabolism; Hypothalamic-pituitary-adrenal axis; Hypothalamo-Hypophyseal System - metabolism; Hypothalamus; IL-1β; Insulin; Insulin - administration & dosage; Insulin - pharmacology; Interleukin 1; Interleukin-1alpha - genetics; Interleukin-1alpha - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Microglia - metabolism; Minocycline; multidisciplinary; Neuronal-glial interactions; Neurons - metabolism; Neuropeptide Y; Neuropeptide Y - metabolism; Neuropeptides; Peptide Fragments - metabolism; Pituitary; Rodents; Science; Science (multidisciplinary); Transcription
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-42728-3

Glucose is a major fuel for the central nervous system and hypoglycemia is a significant homeostatic stressor, which elicits counterregulatory reactions. Hypothalamic metabolic- and stress-related neurons initiate these actions, however recruitment of glia in control such adaptive circuit remain unknown. Groups of fed- and fasted-, vehicle-injected, and fasted + insulin-injected male mice were compared in this study. Bolus insulin administration to fasted mice resulted in hypoglycemia, which increased hypothalamo-pituitary-adrenal (HPA) axis- and sympathetic activity, increased transcription of neuropeptide Y (
Npy
) and agouti-related peptide (
Agrp
) in the hypothalamic arcuate nucleus and activated IBA1+ microglia in the hypothalamus. Activated microglia were found in close apposition to hypoglycemia-responsive NPY neurons. Inhibition of microglia by minocycline increased counterregulatory sympathetic response to hypoglycemia. Fractalkine-CX3CR1 signaling plays a role in control of microglia during hypoglycemia, because density and solidity of IBA1-ir profiles was attenuated in fasted, insulin-treated, CX3CR1 KO mice, which was parallel with exaggerated neuropeptide responses and higher blood glucose levels following insulin administration. Hypoglycemia increased
Il-1b
expression in the arcuate nucleus, while IL-1a/b knockout mice display improved glycemic control to insulin administration. In conclusion, activated microglia in the arcuate nucleus interferes with central counterregulatory responses to hypoglycemia. These results underscore involvement of microglia in hypothalamic regulation of glucose homeostasis.